Quinolone compound and pharmaceutical composition

ABSTRACT

The present invention provides a quinolone compound that inhibits the chronic progression of Parkinson&#39;s disease or protects dopamine neurons from disease etiology, thereby suppressing the progression of neurological dysfunction, so as to prolong the period of time until L-dopa is administered while also improving neuronal function; the quinolone compound of the invention is represented by Formula (1): 
                         
wherein:
         R 1  represents hydrogen or the like;   R 2  represents hydrogen or the like;   R 3  represents substituted or unsubstituted phenyl or the like;   R 4  represents halogen or the like;   R 5  represents hydrogen or the like;   R 6  represents hydrogen or the like; and   R 7  represents hydrogen or the like.

TECHNICAL FIELD

The present invention relates to quinolone compounds and pharmaceuticalcompositions.

BACKGROUND ART

Parkinson's disease is a chronic, progressive neurodegenerative diseasethat generally develops after middle age. Initial symptoms includeunilateral resting tremor, akinesia and rigidity. The tremors, akinesia,and rigidity are called the three major signs of Parkinson's disease,and each of them is caused by the selective death of dopaminergicneurons projected from the substantia nigra to the striatum. Theetiology of the disease is still unknown; however, accumulated evidencesuggests that an impaired energy-generating system accompanied byabnormal mitochondrial function of nigrostriatal dopaminergic neuronstriggers the neurodegenerative disorder of the disease. Themitochondrial dysfunction has been assumed to subsequently causeoxidative stress and failure of calcium homeostasis, thereby resultingin neurodegeneration (Non-Patent Document 1).

Treatments of Parkinson's disease are roughly classified into medicalmanagement (medication) and surgical management (stereotaxic operation).Of these, medication is an established therapy and regarded as a basictreatment. In the medication, a symptomatic therapeutic agent is used tocompensate for the nigrostriatal dopaminergic neuronal functiondenatured by Parkinson's disease. L-dopa exhibits the most remarkabletherapeutic effects. It is said that no agent exceeds the effectivenessof L-dopa. Currently, L-dopa is used together with a dopa decarboxylaseinhibitor to prevent the metabolism thereof in the periphery, and thedesired clinical effects have been obtained.

However, L-dopa treatment has drawbacks in that, after several years ofusage, there is a recurrence of movement disorders such as dyskinesia,and the sustainability and stability of the drug's effects are lost,resulting in fluctuations within each day. Moreover, side effectsincluding digestive problems such as nausea and vomiting brought on byexcessive release of dopamine, circulatory organ problems such asorthostatic hypotension, tachycardia and arrhythmia, and neurologicalmanifestations such as hallucination, delusion and distraction have beena cause for concern.

Thus, in order to decrease the L-dopa preparation dosage and therebyreduce the side effects, multidrug therapies, in which dopamine receptoragonists, dopamine metabolism enzyme inhibitors, dopamine releasers,central anticholinergic agents and the like are used in combination, areemployed. While such therapeutic advances remarkably improve prognoses,there is still no fundamental cure for Parkinson's disease and otherneurodegenerative diseases. Medication must be taken for the rest of thepatient's life, and the aforementioned drawbacks, i.e., decreasedefficacy during long-term administration, side effects, anduncontrollable disease progression, can result from L-dopa monotherapy.In addition, it is difficult to expect dramatic effects, even with theemployment of multidrug therapies.

Alzheimer's disease is a progressive neurodegenerative disease thataffects various cognitive functions, primarily causing impairment ofmemory. Pathologically, Alzheimer's disease is characterized by thedegeneration of synapses or neurons in the hippocampus and cerebralcortex, and the accumulation of two types of abnormal fibrils, i.e.,senile plaques and changes in neurofibrils. Although the diseaseetiology is not completely understood, amyloid β protein (Aβ), which isderived from amyloid precursor protein (APP) by various mechanisms, isknown to play an important role. Currently, cholinesterase inhibitors(tacrine, Aricept, rivastigmine, and galantamine) are used in thetreatment of Alzheimer's disease for ameliorating symptoms, becauseacetylcholinergic nervous system in the brain is involved in cognitivefunction, and marked deficits in the acetylcholinergic system areobserved in Alzheimer's disease. N-methyl-D-aspartate glutamate receptorantagonists (memantine) are also in practical use becausehyperexcitability of the mechanism of glutamate neurotransmission isassociated with neural degeneration or impairment. Neither monotherapynor combination therapy using these drugs, however, has producedsufficient therapeutic effects, nor are they capable of halting theprogression of the disease. Furthermore, gastrointestinal symptoms suchas nausea and diarrhea are observed as side effects of cholinesterase.

With respect to ischemic neurodegenerative disorders induced by cerebralinfarctions, such as atherothrombotic cerebral infarction, lacunarinfarction, cardiogenic cerebral embolism, etc., the usage of very earlythrombolytic therapy using tissue plasminogen activator (tPA) is rapidlyincreasing. This therapy, however, has many problems including a windowas short as within three hours after the onset of disease, hemorrhagiccomplications, etc. In Japan, a free radical scavenger, edaravone, isused for a brain protection therapy. Although edaravone can be usedconcomitantly with tPA, sufficient clinical results have not beenobtained.

Accordingly, there exists a strong need for a pharmaceutical agenthaving a novel mechanism of action, or a neuroprotectant for preventingneural degeneration or impairment from its etiologies such as abnormalmitochondrial function, etc.

CITATION LIST Non Patent Literature

-   NPL 1: Ann. N.Y. Acad. Sci. 991: 111-119 (2003)

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a novel compound thatinhibits the chronic progression of Parkinson's disease or protectsdopamine neurons from the disease itself, thereby suppressing theprogression of neurological dysfunction, so as to prolong the period oftime until L-dopa is administered while also improving neuronalfunction.

Another object of the invention is to provide an agent that is useful intreating diseases that induce cell death, and more specifically, toprovide an agent having efficacy for treating Alzheimer's disease, orimproving dysfunction or neurologic deficits induced by cerebralapoplexy.

Solution to Problem

The present inventors conducted extensive research to accomplish theaforementioned object. Consequently, they succeeded in producing acompound represented by Formula (1) shown below, which protects andimproves mitochondrial function, and/or protects neurons and repairsneuronal function. The present invention has been accomplished based onthe above findings.

The invention provides a quinolone compound, a process for producing thesame, and a pharmaceutical composition as set forth in the followingItems 1 to 23.

Item 1. A quinolone compound represented by Formula (1):

or a salt thereof,wherein R₁ represents:(1) hydrogen,(2) lower alkyl,(3) halogen-substituted lower alkyl,(4) lower alkenyl,(5) lower alkanoyl,(6) halogen-substituted lower alkanoyl,(7) hydroxy lower alkyl,(8) protected hydroxy lower alkyl,(9) hydroxy lower alkanoyl,(10) protected hydroxy lower alkanoyl,(11) lower alkylthio lower alkyl,(12) amino lower alkylthio lower alkyl optionally having one or morelower alkyl groups,(13) hydroxy lower alkylthio lower alkyl,(14) carboxy lower alkylthio lower alkyl,(15) lower alkoxycarbonyl lower alkylthio lower alkyl,(16) amino lower alkylthiocarbonyl lower alkyl optionally having one ormore lower alkyl groups,(17) hydroxy lower alkylsulfonyl lower alkyl,(18) carboxy lower alkylsulfonyl lower alkyl,(19) lower alkoxycarbonyl lower alkylsulfonyl lower alkyl,(20) lower alkanoyl lower alkylsulfonyl lower alkyl,(21) piperazinyl lower alkylsulfonyl lower alkyl optionally having oneor more lower alkyl groups on the piperazine ring,(22) piperazinylcarbonyl lower alkylsulfonyl lower alkyl optionallyhaving one or more lower alkyl groups on the piperazine ring,(23) lower alkanoyl lower alkyl,(24) carboxy lower alkyl,(25) lower alkoxycarbonyl lower alkyl,(26) piperazinyl lower alkoxycarbonyl lower alkyl optionally having oneor more lower alkyl groups on the piperazine ring,(27) morpholinyl lower alkyl,(28) oxazepanyl lower alkyl,(29) amino lower alkyl optionally having one or more lower alkyl groups,(30) piperazyl lower alkyl optionally having, on the piperazine ring,one or more substituents selected from the group consisting of loweralkyl, lower alkoxy lower alkyl, and pyridyl,(31) piperidyl lower alkyl optionally having one or more morpholinylgroups,(32) azetidyl lower alkyl optionally having one or more hydroxy groupson the azetidine ring,(33) isoindolinyl lower alkyl optionally having one or more oxo groups,(34) amino lower alkanoyloxy lower alkyl optionally having one or moresubstituents selected from the group consisting of lower alkyl and loweralkoxycarbonyl,(35) carbamoyl lower alkyl optionally having one or more substituentsselected from lower alkyl; morpholinyl lower alkyl; piperidyl optionallyhaving one or more substituents selected from the group consisting oflower alkyl and lower alkoxycarbonyl; and piperazinyl lower alkyloptionally having one or more lower alkyl groups,(36) phosphonooxy lower alkyl optionally having one or morehydroxy-protecting groups,(37) phosphonooxy lower alkanoyloxy lower alkyl optionally having one ormore hydroxy-protecting groups,(38) benzoyloxy lower alkyl optionally having, on the benzene ring, oneor more substituents selected from the group consisting of hydroxy,protected hydroxy, and phosphonooxy optionally having one or morehydroxyl-protecting groups,(39) tetrahydropyranyl optionally having one or more substituentsselected from the group consisting of hydroxy, hydroxy lower alkyl andcarboxyl, or(40) lower alkanoylamino lower alkyl optionally having, on the loweralkanoyl group, one or more substituents selected from the groupconsisting of halogen; hydroxy; amino; lower alkoxycarbonylamino;piperazinyl optionally having one or more lower alkoxy lower alkylgroups; imidazolyl; and morpholinylpiperidyl;

R₂ represents:

(1) hydrogen,

(2) lower alkyl,

(3) lower alkanoyl,

(4) hydroxy lower alkyl,

(5) carboxy,

(6) lower alkoxycarbonyl,

(7) carbamoyl optionally having one or more substituents selected fromthe group consisting of lower alkyl; halogen-substituted lower alkyl;hydroxy lower alkyl; piperazinyl lower alkyl optionally having one ormore lower alkyl groups; and morpholinyl lower alkyl,(8) carbamoyl lower alkyl optionally having one or more lower alkylgroups,(9) morpholinyl lower alkyl,(10) piperazinyl lower alkyl optionally having one or more substituentsselected from the group consisting of lower alkyl and pyridyl optionallyhaving one or more lower alkyl groups,(11) diazepanyl lower alkyl,(12) amino lower alkyl optionally having one or more substituentsselected from the group consisting of lower alkyl, halogen-substitutedlower alkyl, hydroxy lower alkyl, and morpholinyl lower alkyl,(13) lower alkoxycarbonyl lower alkyl, or(14) carboxy lower alkyl;

R₃ represents phenyl, thienyl, furyl, pyrazolyl, or pyrimidinyl,wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one or more substituents selected from the group consisting of thefollowing substituents (1) to (14):

(1) lower alkyl,

(2) lower alkoxy,

(3) lower alkanoyl,

(4) halogen,

(5) hydroxy,

(6) hydroxy lower alkyl,

(7) hydroxy lower alkoxy,

(8) protected hydroxy lower alkoxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl lower alkoxy optionally having one or more lower alkylgroups,

(13) carbamoyl optionally having one or more morpholinyl lower alkylgroups, and

(14) morpholinylpiperidylcarbonyl;

R₄ represents halogen, lower alkyl, or lower alkoxy;

R₅ represents hydrogen or halogen;

R₄ and R₅ may be linked to form a group represented by any of thefollowing formulae:

or a group represented by the following formula:

the group optionally having one or more substituents selected from thegroup consisting of lower alkyl and oxo groups;

R₆ represents hydrogen or lower alkoxy;

R₇ represents any of the following groups (1) to (11):

(1) hydrogen,

(2) lower alkoxy,

(3) hydroxy lower alkoxy,

(4) protected hydroxy lower alkoxy,

(5) lower alkoxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having one or more substituentsselected from the group consisting of lower alkyl and morpholinyl loweralkyl,

(7) amino optionally having one or two substituents selected from thegroup consisting of lower alkyl and cyclo C₃-C₈ alkyl,

(8) cyclo C₃-C₈ alkyloxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy, and

(11) pyrrolidinyl; and

R₆ and R₇ may be linked to form a group represented by any of thefollowing formulae:

Item 2. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 1, wherein:

R₄ and R₅ may be linked to form a group represented by any of thefollowing formulae:

or a group represented by the following formula:

the group optionally having one or two substituents selected from thegroup consisting of lower alkyl or oxo groups.

Item 3. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 2, wherein:

R₁ represents:

(1) hydrogen,

(2) lower alkyl,

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) lower alkanoyl,

(6) halogen-substituted lower alkanoyl,

(7) hydroxy lower alkyl,

(8) phenyl lower alkoxy lower alkyl,

(9) hydroxy lower alkanoyl,

(10) phenyl lower alkoxy lower alkanoyl,

(11) lower alkylthio lower alkyl,

(12) amino lower alkylthio lower alkyl optionally having, on the aminogroup, two lower alkyl groups,

(13) hydroxy lower alkylthio lower alkyl,

(14) carboxy lower alkylthio lower alkyl,

(15) lower alkoxycarbonyl lower alkylthio lower alkyl,

(16) amino lower alkylthiocarbonyl lower alkyl optionally having, on theamino group, two lower alkyl groups,

(17) hydroxy lower alkylsulfonyl lower alkyl,

(18) carboxy lower alkylsulfonyl lower alkyl,

(19) lower alkoxycarbonyl lower alkylsulfonyl lower alkyl,

(20) lower alkanoyl lower alkylsulfonyl lower alkyl,

(21) piperazinyl lower alkylsulfonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(22) piperazinylcarbonyl lower alkylsulfonyl lower alkyl optionallyhaving one lower alkyl group on the piperazine ring,

(23) lower alkanoyl lower alkyl,

(24) carboxy lower alkyl,

(25) lower alkoxycarbonyl lower alkyl,

(26) piperazinyl lower alkoxycarbonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(27) morpholinyl lower alkyl,

(28) oxazepanyl lower alkyl,

(29) amino lower alkyl optionally having one lower alkyl group on theamino group,

(30) piperazyl lower alkyl optionally having, on the piperazine ring,one substituent selected from the group consisting of lower alkyl, loweralkoxy lower alkyl, and pyridyl,

(31) piperidyl lower alkyl optionally having one morpholinyl group onthe piperidine ring,

(32) azetidyl lower alkyl optionally having one hydroxy group on theazetidine ring,

(33) isoindolinyl lower alkyl optionally having two oxo groups on theisoindoline ring,

(34) amino lower alkanoyloxy lower alkyl optionally having, on the aminogroup, one or two substituents selected from the group consisting oflower alkyl and lower alkoxycarbonyl,

(35) carbamoyl lower alkyl optionally having, on the carbamoyl group,one substituent selected from lower alkyl; morpholinyl lower alkyl;piperidyl optionally having one substituent selected from the groupconsisting of lower alkyl and lower alkoxycarbonyl; and piperazinyllower alkyl optionally having one lower alkyl group,(36) phosphonooxy lower alkyl optionally having one or two lower alkylgroups on the phosphonooxy group,(37) phosphonooxy lower alkanoyloxy lower alkyl optionally having one ortwo lower alkyl groups on the phosphonooxy group,(38) benzoyloxy lower alkyl optionally having, on the benzene ring, onesubstituent selected from the group consisting of hydroxy, benzyloxy,and phosphonooxy optionally having one or two lower alkyl groups,(39) tetrahydropyranyl optionally having three hydroxy groups and onehydroxy lower alkyl group, or(40) lower alkanoylamino lower alkyl optionally having, on the loweralkanoyl group, one or two substituents selected from the groupconsisting of halogen; hydroxy; amino; lower alkoxycarbonylamino;piperazinyl optionally having one lower alkoxy lower alkyl group;imidazolyl; and morpholinylpiperidyl;

R₂ represents:

(1) hydrogen,

(2) lower alkyl,

(3) lower alkanoyl,

(4) hydroxy lower alkyl,

(5) carboxy,

(6) lower alkoxycarbonyl,

(7) carbamoyl optionally having one or two substituents selected fromthe group consisting of lower alkyl; halogen-substituted lower alkyl;hydroxy lower alkyl; piperazinyl lower alkyl optionally having one loweralkyl group on the piperazine ring; and morpholinyl lower alkyl,(8) carbamoyl lower alkyl optionally having one lower alkyl group on thecarbamoyl group,(9) morpholinyl lower alkyl,(10) piperazinyl lower alkyl optionally having, on the piperazine ring,one substituent selected from the group consisting of lower alkyl andpyridyl optionally having one lower alkyl group,(11) diazepanyl lower alkyl, or(12) amino lower alkyl optionally having, on the amino group, one or twosubstituents selected from the group consisting of lower alkyl,halogen-substituted lower alkyl, hydroxy lower alkyl, and morpholinyllower alkyl;

R₃ represents phenyl, thienyl, furyl, pyrazolyl, or pyrimidinyl,wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one or two substituents selected from the group consisting of thefollowing substituents (1) to (14):

(1) lower alkyl,

(2) lower alkoxy,

(3) lower alkanoyl,

(4) halogen,

(5) hydroxy,

(6) hydroxy lower alkyl,

(7) hydroxy lower alkoxy,

(8) tetrahydropyranyloxy lower alkoxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl lower alkoxy optionally having one lower alkyl group onthe carbamoyl group,

(13) carbamoyl optionally having one morpholinyl lower alkyl group, and

(14) morpholinylpiperidylcarbonyl;

R₆ represents hydrogen or lower alkoxy; and

R₇ represents any of the following groups (1) to (11):

(1) hydrogen,

(2) lower alkoxy,

(3) hydroxy lower alkoxy,

(4) benzyloxy lower alkoxy,

(5) lower alkoxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having, on the carbamoyl group,one substituent selected from the group consisting of lower alkyl andmorpholinyl lower alkyl,

(7) amino optionally having two substituents selected from the groupconsisting of lower alkyl and cyclo C₃-C₈ alkyl,

(8) cyclo C₃-C₈ alkyloxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy, and

(11) pyrrolidinyl.

Item 4. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 3, wherein R₁ represents:

(1) hydrogen,

(2) lower alkyl,

(3) halogen-substituted lower alkyl,

(24) carboxy lower alkyl,

(25) lower alkoxycarbonyl lower alkyl,

(27) morpholinyl lower alkyl,

(28) oxazepanyl lower alkyl,

(30) piperazyl lower alkyl optionally having, on the piperazine ring,one lower alkoxy lower alkyl,

(31) piperidyl lower alkyl,

(35) carbamoyl lower alkyl optionally having one morpholinyl loweralkyl, or

(36) phosphonooxy lower alkyl optionally having one or two lower alkylgroups

R₂ represents:

(1) hydrogen, or

(2) lower alkyl,

R₃ represents phenyl, thienyl, or furyl, wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one lower alkoxy group,

R₆ represents hydrogen; and

R₇ represents lower alkoxy.

Item 5. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 1, wherein

R₆ and R₇ may be linked to form a group represented by any of thefollowing formulae:

Item 6. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 5, wherein

R₁ represents:

(1) hydrogen,

(2) lower alkyl, or

(36) phosphonooxy lower alkyl optionally having one or two lower alkylgroups;

R₂ represents hydrogen,

R₃ represents phenyl wherein the aromatic or heterocyclic ringrepresented by R₃ may be substituted with one lower alkoxy group;

R₄ represents lower alkyl, or lower alkoxy; and

R₅ represents hydrogen.

Item 7. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 1, wherein

R₁ represents:

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) lower alkanoyl,

(6) halogen-substituted lower alkanoyl,

(7) hydroxy lower alkyl,

(8) phenyl lower alkoxy lower alkyl,

(9) hydroxy lower alkanoyl,

(10) phenyl lower alkoxy lower alkanoyl,

(11) lower alkylthio lower alkyl,

(12) amino lower alkylthio lower alkyl optionally having one or twolower alkyl groups,

(13) hydroxy lower alkylthio lower alkyl,

(14) carboxy lower alkylthio lower alkyl,

(15) lower alkoxycarbonyl lower alkylthio lower alkyl,

(16) amino lower alkylthiocarbonyl lower alkyl optionally having one ortwo lower alkyl groups,

(17) hydroxy lower alkylsulfonyl lower alkyl,

(18) carboxy lower alkylsulfonyl lower alkyl,

(19) lower alkoxycarbonyl lower alkylsulfonyl lower alkyl,

(20) lower alkanoyl lower alkylsulfonyl lower alkyl,

(21) piperazinyl lower alkylsulfonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(22) piperazinylcarbonyl lower alkylsulfonyl lower alkyl optionallyhaving one lower alkyl group on the piperazine ring,

(23) lower alkanoyl lower alkyl,

(24) carboxy lower alkyl,

(25) lower alkoxycarbonyl lower alkyl,

(26) piperazinyl lower alkoxycarbonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(27) morpholinyl lower alkyl,

(28) oxazepanyl lower alkyl,

(29) amino lower alkyl optionally having one or two lower alkyl groups,

(30) piperazyl lower alkyl optionally having, on the piperazine ring,one substituent selected from the group consisting of lower alkyl, loweralkoxy lower alkyl, and pyridyl,

(31) piperidyl lower alkyl optionally having one morpholinyl group,

(32) azetidyl lower alkyl optionally having one hydroxy group on theazetidine ring,

(33) isoindolinyl lower alkyl optionally having one or two oxo groups,

(34) amino lower alkanoyloxy lower alkyl optionally having one or twosubstituents selected from the group consisting of lower alkyl and loweralkoxycarbonyl,

(35) carbamoyl lower alkyl optionally having one or two substituentsselected from lower alkyl; morpholinyl lower alkyl; piperidyl optionallyhaving one substituent selected from the group consisting of lower alkyland lower alkoxycarbonyl; and piperazinyl lower alkyl optionally havingone lower alkyl group,(36) phosphonooxy lower alkyl optionally having one or two lower alkylgroups on the phosphonooxy group,(37) phosphonooxy lower alkanoyloxy lower alkyl optionally having one ortwo lower alkyl groups on the phosphonooxy group,(38) benzoyloxy lower alkyl optionally having, on the benzene ring, onesubstituent selected from the group consisting of hydroxy, benzyloxy,and phosphonooxy optionally having one or two lower alkyl groups,(39) tetrahydropyranyl optionally having one to four substituentsselected from the group consisting of hydroxy, hydroxy lower alkyl andcarboxyl, or(40) lower alkanoylamino lower alkyl optionally having, on the loweralkanoyl group, one or two substituents selected from the groupconsisting of halogen; hydroxy; amino; lower alkoxycarbonylamino;piperazinyl optionally having one lower alkoxy lower alkyl group;imidazolyl; and morpholinylpiperidyl;

R₂ represents:

(1) hydrogen,

(2) lower alkyl,

(3) lower alkanoyl,

(4) hydroxy lower alkyl,

(5) carboxy,

(6) lower alkoxycarbonyl,

(7) carbamoyl optionally having one or two substituents selected fromthe group consisting of lower alkyl; halogen-substituted lower alkyl;hydroxy lower alkyl; piperazinyl lower alkyl optionally having one loweralkyl group on the piperazine ring; and morpholinyl lower alkyl,(8) carbamoyl lower alkyl optionally having one lower alkyl group on thecarbamoyl group,(9) morpholinyl lower alkyl,(10) piperazinyl lower alkyl optionally having, on the piperazine ring,one substituent selected from the group consisting of lower alkyl andpyridyl optionally having one lower alkyl group,(11) diazepanyl lower alkyl, or(12) amino lower alkyl optionally having, on the amino group, one or twosubstituents selected from the group consisting of lower alkyl,halogen-substituted lower alkyl, hydroxy lower alkyl, and morpholinyllower alkyl;

R₃ represents phenyl, thienyl, furyl, pyrazolyl, or pyrimidinyl,wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one or two substituents selected from the group consisting of thefollowing substituents (1) to (14):

(1) lower alkyl,

(2) lower alkoxy,

(3) lower alkanoyl,

(4) halogen,

(5) hydroxy,

(6) hydroxy lower alkyl,

(7) hydroxy lower alkoxy,

(8) tetrahydropyranyloxy lower alkoxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl lower alkoxy optionally having one or two lower alkylgroups,

(13) carbamoyl optionally having one morpholinyl lower alkyl group, and

(14) morpholinylpiperidylcarbonyl;

R₄ represents halogen, lower alkyl, or lower alkoxy;

R₅ represents hydrogen or halogen;

R₆ represents hydrogen or lower alkoxy; and

R₇ represents any of the following groups (1) to (11):

(1) hydrogen,

(2) lower alkoxy,

(3) hydroxy lower alkoxy,

(4) benzyloxy lower alkoxy,

(5) lower alkoxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having one substituent selectedfrom the group consisting of lower alkyl and morpholinyl lower alkyl,

(7) amino optionally having one or two substituents selected from thegroup consisting of lower alkyl and cyclo C₃-C₈ alkyl,

(8) cyclo C₃-C₈ alkyloxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy, and

(11) pyrrolidinyl.

Item 8. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 7, wherein

R₁ represents:

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) lower alkanoyl,

(6) halogen-substituted lower alkanoyl,

(8) benzyloxy lower alkyl,

(10) benzyloxy lower alkanoyl,

(11) lower alkylthio lower alkyl,

(12) amino lower alkylthio lower alkyl optionally having one or twolower alkyl groups,

(13) hydroxy lower alkylthio lower alkyl,

(14) carboxy lower alkylthio lower alkyl,

(15) lower alkoxycarbonyl lower alkylthio lower alkyl,

(16) amino lower alkylthiocarbonyl lower alkyl optionally having one ortwo lower alkyl groups,

(17) hydroxy lower alkylsulfonyl lower alkyl,

(18) carboxy lower alkylsulfonyl lower alkyl,

(19) lower alkoxycarbonyl lower alkylsulfonyl lower alkyl,

(20) lower alkanoyl lower alkylsulfonyl lower alkyl,

(21) piperazinyl lower alkylsulfonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(22) piperazinylcarbonyl lower alkylsulfonyl lower alkyl optionallyhaving one lower alkyl group on the piperazine ring,

(24) carboxy lower alkyl,

(25) lower alkoxycarbonyl lower alkyl,

(26) piperazinyl lower alkoxycarbonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(27) morpholinyl lower alkyl,

(29) amino lower alkyl optionally having one or two lower alkyl groups,

(30) piperazyl lower alkyl optionally having, on the piperazine ring,one substituent selected from the group consisting of lower alkyl, loweralkoxy lower alkyl, and pyridyl,

(31) piperidyl lower alkyl optionally having one morpholinyl group,

(32) azetidyl lower alkyl optionally having one hydroxy group on theazetidine ring,

(33) isoindolinyl lower alkyl optionally having one or two oxo groups,

(34) amino lower alkanoyloxy lower alkyl optionally having one or twosubstituents selected from the group consisting of lower alkyl and loweralkoxycarbonyl,

(35) carbamoyl lower alkyl optionally having one or two substituentsselected from lower alkyl; morpholinyl lower alkyl; piperidyl optionallyhaving one substituent selected from the group consisting of lower alkyland lower alkoxycarbonyl; and piperazinyl lower alkyl optionally havingone lower alkyl group,(36) phosphonooxy lower alkyl optionally having one or two lower alkylgroups on the phosphonooxy group,(37) phosphonooxy lower alkanoyloxy lower alkyl optionally having one ortwo lower alkyl groups on the phosphonooxy group,(38) benzoyloxy lower alkyl optionally having, on the benzene ring, onesubstituent selected from the group consisting of hydroxy, benzyloxy,and phosphonooxy optionally having one or two lower alkyl groups,(39) tetrahydropyranyl optionally having one or four substituentsselected from the group consisting of hydroxy, hydroxy lower alkyl andcarboxyl, or(40) lower alkanoylamino lower alkyl optionally having, on the loweralkanoyl group, one or two substituents selected from the groupconsisting of halogen; hydroxy; amino; lower alkoxycarbonylamino;piperazinyl optionally having one lower alkoxy lower alkyl group;imidazolyl; and morpholinylpiperidyl;

R₂ represents hydrogen;

R₃ represents phenyl, pyrazolyl, or pyrimidinyl, wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one or two substituents selected from the group consisting of thefollowing substituents (1), (2), (4), (5), (7), (8), (10), (11), and(12):

(1) lower alkyl,

(2) lower alkoxy,

(4) halogen,

(5) hydroxy,

(7) hydroxy lower alkoxy,

(8) tetrahydropyranyloxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(11) pyrrolidinylcarbonyl, and

(12) carbamoyl lower alkoxy;

R₄ represents halogen;

R₅ represents hydrogen or halogen;

R₆ represents hydrogen; and

R₇ represents any of the following groups (2), (7), (8) and (11):

(2) lower alkoxy,

(7) amino optionally having one or two substituents selected from thegroup consisting of lower alkyl and cyclo C₃-C₈ alkyl,

(8) cyclo C₃-C₈ alkyloxy, and

(11) pyrrolidinyl.

Item 9. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 1, wherein

R₁ represents:

(1) hydrogen, or

(2) lower alkyl;

R₂ represents:

(3) lower alkanoyl,

(4) hydroxy lower alkyl,

(5) carboxy,

(6) lower alkoxycarbonyl,

(7) carbamoyl optionally having one or two substituents selected fromthe group consisting of lower alkyl; halogen-substituted lower alkyl;hydroxy lower alkyl; piperazinyl lower alkyl optionally having one loweralkyl group; and morpholinyl lower alkyl,

(8) carbamoyl lower alkyl optionally having one lower alkyl group,

(9) morpholinyl lower alkyl,

(10) piperazinyl lower alkyl optionally having one substituent selectedfrom the group consisting of lower alkyl and pyridyl optionally havingone lower alkyl group,

(11) diazepanyl lower alkyl,

(12) amino lower alkyl optionally having one or two substituentsselected from the group consisting of lower alkyl, halogen-substitutedlower alkyl, hydroxy lower alkyl, and morpholinyl lower alkyl,

(13) lower alkoxycarbonyl lower alkyl, or

(14) carboxy lower alkyl;

R₃ represents phenyl, thienyl, furyl, pyrazolyl, or pyrimidinyl,wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one substituent selected from the group consisting of the followingsubstituents (1) to (14):

(1) lower alkyl,

(2) lower alkoxy,

(3) lower alkanoyl,

(4) halogen,

(5) hydroxy,

(6) hydroxy lower alkyl,

(7) hydroxy lower alkoxy,

(8) protected hydroxy lower alkoxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl lower alkoxy optionally having one lower alkyl group,

(13) carbamoyl optionally having one morpholinyl lower alkyl group, and

(14) morpholinylpiperidylcarbonyl;

R₄ represents halogen, lower alkyl, or lower alkoxy;

R₅ represents hydrogen or halogen;

R₆ represents hydrogen or lower alkoxy; and

R₇ represents any of the following groups (1) to (11):

(1) hydrogen,

(2) lower alkoxy,

(3) hydroxy lower alkoxy,

(4) benzyloxy lower alkoxy,

(5) lower alkoxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having one substituent selectedfrom the group consisting of lower alkyl and morpholinyl lower alkyl,

(7) amino optionally having one or two substituents selected from thegroup consisting of lower alkyl and cyclo C₃-C₈ alkyl,

(8) cyclo C₃-C₈ alkyloxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy, and

(11) pyrrolidinyl.

Item 10. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 9, wherein

R₁ represents hydrogen;

R₂ represents:

(3) lower alkanoyl,

(4) hydroxy lower alkyl,

(5) carboxy,

(6) lower alkoxycarbonyl,

(7) carbamoyl optionally having one or two substituents selected fromthe group consisting of lower alkyl; halogen-substituted lower alkyl;hydroxy lower alkyl; piperazinyl lower alkyl optionally having one loweralkyl group; and morpholinyl lower alkyl,

(8) carbamoyl lower alkyl optionally having one lower alkyl group,

(9) morpholinyl lower alkyl,

(10) piperazinyl lower alkyl optionally having one substituent selectedfrom the group consisting of lower alkyl and pyridyl optionally havingone lower alkyl group,

(11) diazepanyl lower alkyl,

(12) amino lower alkyl optionally having one or two substituentsselected from the group consisting of lower alkyl, halogen-substitutedlower alkyl, hydroxy lower alkyl, and morpholinyl lower alkyl, or

(14) carboxy lower alkyl;

R₃ represents phenyl, wherein:

the phenyl represented by R₃ is substituted with one lower alkoxy group,

R₄ represents halogen;

R₅ represents hydrogen;

R₆ represents hydrogen; and

R₇ represents lower alkoxy.

Item 11. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 1, wherein

R₁ represents:

(1) hydrogen, or

(2) lower alkyl;

R₂ represents hydrogen;

R₃ represents phenyl, thienyl, furyl, pyrazolyl, or pyrimidinyl,wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one substituent selected from the group consisting of the followingsubstituents (7), (8), (9), (10), (12), (13) and (14):

(7) hydroxy lower alkoxy,

(8) benzyloxy lower alkoxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(12) carbamoyl lower alkoxy optionally having one lower alkyl group,

(13) carbamoyl optionally having one morpholinyl lower alkyl group, and

(14) morpholinylpiperidylcarbonyl;

R₄ represents halogen, lower alkyl, or lower alkoxy;

R₅ represents hydrogen or halogen;

R₆ represents hydrogen or lower alkoxy; and

R₇ represents any of the following groups (1) to (11):

(1) hydrogen,

(2) lower alkoxy,

(3) hydroxy lower alkoxy,

(4) benzyloxy lower alkoxy,

(5) lower alkoxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having one substituent selectedfrom the group consisting of lower alkyl and morpholinyl lower alkyl,

(7) amino optionally having one or two substituents selected from thegroup consisting of lower alkyl and cyclo C₃-C₈ alkyl,

(8) cyclo C₃-C₈ alkyloxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy, and

(11) pyrrolidinyl.

Item 12. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 11, wherein

R₁ represents hydrogen;

R₃ represents phenyl, wherein:

the phenyl represented by R₃ may be substituted with one substituentselected from the group consisting of the following substituents (7) to(14):

(7) hydroxy lower alkoxy,

(8) benzyloxy lower alkoxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl lower alkoxy optionally having one lower alkyl group,

(13) carbamoyl optionally having one morpholinyl lower alkyl group, and

(14) morpholinylpiperidylcarbonyl;

R₄ represents halogen;

R₅ represents hydrogen;

R₆ represents hydrogen; and

R₇ represents any of the following groups (2) and (11):

(2) lower alkoxy; and

(11) pyrrolidinyl.

Item 13. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 1, wherein

R₁ represents:

(1) hydrogen or

(2) lower alkyl;

R₂ represents hydrogen;

R₃ represents phenyl, wherein:

the phenyl represented by R₃ is substituted with one lower alkoxy,

R₄ represents halogen, lower alkyl, or lower alkoxy;

R₅ represents hydrogen or halogen;

R₆ represents hydrogen or lower alkoxy; and

R₇ represents any of the following groups (4), (6), (9) and (10):

(4) benzyloxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having one substituent selectedfrom the group consisting of lower alkyl and morpholinyl lower alkyl,

(9) carboxy lower alkoxy, and

(10) lower alkoxycarbonyl lower alkoxy.

Item 14. A quinolone compound of General Formula (1) or a salt thereofaccording to Item 13, wherein

R₁ represents hydrogen;

R₃ represents phenyl, wherein:

the phenyl represented by R₃ may be substituted with one lower alkoxy,

R₄ represents halogen;

R₅ represents hydrogen;

R₆ represents hydrogen; and

R₇ represents any of the following groups (4), (6), (9), (10) and (11):

(4) benzyloxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having one substituent selectedfrom the group consisting of lower alkyl and morpholinyl lower alkyl,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy, and

(11) pyrrolidinyl.

Item 15. A pharmaceutical composition comprising a quinolone compound ofGeneral Formula (1) of any one of Items 1 to 14 or a salt thereof as anactive ingredient; and a pharmaceutically acceptable carrier.

Item 16. A prophylactic and/or therapeutic agent for neurodegenerativediseases, diseases induced by neurological dysfunction, or diseasesinduced by deterioration of mitochondrial function, the agent comprisingas an active ingredient a quinolone compound of General Formula (1) ofany one of Items 1 to 14 or a salt thereof.

Item 17. A prophylactic and/or therapeutic agent according to Item 16,wherein the neurodegenerative disease is selected from the groupconsisting of Parkinson's disease, Parkinson's syndrome, juvenileparkinsonism, striatonigral degeneration, progressive supranuclearpalsy, pure akinesia, Alzheimer's disease, Pick's disease, priondisease, corticobasal degeneration, diffuse Lewy body disease,Huntington's disease, chorea-acanthocytosis, benign hereditary chorea,paroxysmal choreoathetosis, essential tremor, essential myoclonus,Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism,dystonia musculorum deformance, athetosis, spasmodic torticollis, Meigesyndrome, cerebral palsy, Wilson's disease, Segawa's disease,Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy,spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-typecerebellar atrophy, olivopontocerebellar atrophy, hereditaryolivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysianatrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's Ataxia,Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia,hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateralsclerosis, progressive bulbar palsy, spinal progressive muscularatrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease,Kugelberg-Welander disease, hereditary spastic paraparesis,syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiffmansyndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy,Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiationmyelopathy, age-related macular degeneration, and cerebral apoplexyselected from the group consisting of cerebral infarction and cerebralhemorrhage and/or associated dysfunction or neurologic deficits.

Item 18. A prophylactic and/or therapeutic agent according to Item 16,wherein the disease induced by neurological dysfunction is selected fromthe group consisting of spinal cord injury, chemotherapy-inducedneuropathy, diabetic neuropathy, radiation damage, and a demyelinatingdisease selected from the group consisting of multiple sclerosis, acutedisseminated encephalomyelitis, transverse myelitis, progressivemultifocal leucoencephalopathy, subacute sclerosing panencephalitis,chronic inflammatory demyelinating polyneuropathy and Guillain-Barresyndrome.

Item 19. A prophylactic and/or therapeutic agent according to Item 16,wherein the disease induced by deterioration of mitochondrial functionis selected from the group consisting of Pearson's syndrome, diabetes,deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELASoverlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy,myopathy, dementia, gastrointestinal ataxia, acquired sideroblasticanemia, aminoglycoside-induced hearing loss, complex III deficiency dueto inherited variants of cytochrome b, multiple symmetrical lipomatosis,ataxia, myoclonus, retinopathy, MNGIE, ANTl disease, Twinkle disease,POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex Ideficiency, complex II deficiency, optic nerve atrophy, fatal infantilecomplex IV deficiency, mitochondrial DNA deficiency, mitochondrial DNAdeficiency syndrome, Leigh's encephalomyelopathy,chronic-progressive-external-ophthalmoplegia syndrome (CPEO),Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria,drug-induced mitochondrial diseases, schizophrenia, major depressiondisorder, bipolar I disorder, bipolar II disorder, mixed episode,dysthymic disorders, atypical depression, seasonal affective disorders,postpartum depression, minor depression, recurrent brief depressivedisorder, intractable depression/chronic depression, double depression,and acute renal failure.

Item 20. A prophylactic and/or therapeutic agent comprising as an activeingredient the compound of any one of Items 1 to 14 or a salt thereof,the prophylactic and/or therapeutic agent being used for treating orpreventing ischemic heart diseases and/or associated dysfunction,cardiac failure, myocardosis, aortic dissection, immunodeficiency,autoimmune diseases, pancreatic insufficiency, diabetes, atheroembolicrenal disease, polycytic kidney, medullary cystic disease, renalcortical necrosis, malignant nephrosclerosis, renal failure, hepaticencephalopathy, liver failure, chronic obstructive pulmonary disease,pulmonary embolism, bronchiectasis, silicosis, black lung, idiopathicpulmonary fibrosis, Stevens-Johnson syndrome, toxic epidermalnecrolysis, muscular dystrophy, clostridial muscle necrosis, and femoralcondyle necrosis.

Item 21. Use of a quinolone compound of General Formula (1) of any oneof Item 1 to 20 or a salt thereof as a drug.

Item 22. A method for treating or preventing neurodegenerative diseases,diseases induced by neurological dysfunction, or diseases induced bydeterioration of mitochondrial function, comprising administering aquinolone compound of General Formula (1) of Item 1 or a salt thereof toa human or an animal.

Item 23. A process for producing a quinolone compound represented byFormula (1b):

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined in Item 1, and R₁′ isa group represented by R₁ as defined in Item 1 other than hydrogen, or asalt thereof; the process comprising reacting a compound represented bythe formula:R₁′—X₂wherein X₂ represents a group that undergoes the same substitutionreaction as that of a halogen or a halogen atom, with a compoundrepresented by the formula:

wherein R₂, R₃, R₄, R₅, R₆ and R₇ are as defined in Item 1.

A further embodiment of the quinolone compound represented by Formula(1) is as follows:

Formula (1):

wherein R₁ represents:

(1) hydrogen,

(2) lower alkyl,

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) lower alkanoyl,

(6) halogen-substituted lower alkanoyl,

(7) hydroxy lower alkyl,

(8) phenyl lower alkoxy lower alkyl,

(9) hydroxy lower alkanoyl,

(10) phenyl lower alkoxy lower alkanoyl,

(11) lower alkylthio lower alkyl,

(12) amino lower alkylthio lower alkyl optionally having, on the aminogroup, one or two, and preferably two, lower alkyl groups;

(13) hydroxy lower alkylthio lower alkyl,

(14) carboxy lower alkylthio lower alkyl,

(15) lower alkoxycarbonyl lower alkylthio lower alkyl,

(16) amino lower alkylthiocarbonyl lower alkyl optionally having, on theamino group, one or two, and preferably two, lower alkyl groups,

(17) hydroxy lower alkylsulfonyl lower alkyl,

(18) carboxy lower alkylsulfonyl lower alkyl,

(19) lower alkoxycarbonyl lower alkylsulfonyl lower alkyl,

(20) lower alkanoyl lower alkylsulfonyl lower alkyl,

(21) piperazinyl lower alkylsulfonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(22) piperazinylcarbonyl lower alkylsulfonyl lower alkyl optionallyhaving one lower alkyl group on the piperazine ring,

(23) lower alkanoyl lower alkyl,

(24) carboxy lower alkyl,

(25) lower alkoxycarbonyl lower alkyl,

(26) piperazinyl lower alkoxycarbonyl lower alkyl optionally having onelower alkyl group on the piperazine ring,

(27) morpholinyl lower alkyl,

(28) oxazepanyl lower alkyl,

(29) amino lower alkyl optionally having one lower alkyl group on theamino group,

(30) piperazyl lower alkyl optionally having, on the piperazine ring,one substituent selected from the group consisting of lower alkyl, loweralkoxy lower alkyl, and pyridyl,

(31) piperidyl lower alkyl optionally having one morpholinyl group onthe piperidine ring,

(32) azetidyl lower alkyl optionally having one hydroxy group on theazetidine ring,

(33) isoindolinyl lower alkyl optionally having two oxo groups on theisoindoline ring,

(34) amino lower alkanoyloxy lower alkyl optionally having, on the aminogroup, one or two substituents selected from the group consisting oflower alkyl and lower alkoxycarbonyl,

(35) carbamoyl lower alkyl optionally having, on the carbamoyl group,one or two substituents selected from lower alkyl; morpholinyl loweralkyl; piperidyl optionally having one substituent selected from thegroup consisting of lower alkyl and lower alkoxycarbonyl; andpiperazinyl lower alkyl optionally having one lower alkyl group,(36) phosphonooxy lower alkyl optionally having one or two lower alkylgroups on the phosphonooxy group,(37) phosphonooxy lower alkanoyloxy lower alkyl optionally having one ortwo lower alkyl groups on the phosphonooxy group,(38) benzoyloxy lower alkyl optionally having, on the benzene ring, onesubstituent selected from the group consisting of hydroxy, protectedhydroxy, and phosphonooxy optionally having one or two lower alkylgroups,(39) tetrahydropyranyl optionally having one to four, and preferablyfour, substituents selected from the group consisting of hydroxy,hydroxy lower alkyl and carboxyl; and, more preferably,tetrahydropyranyl having three hydroxy groups and one hydroxy loweralkyl group, or(40) lower alkanoylamino lower alkyl optionally having, on the loweralkanoyl group, one or two substituents selected from the groupconsisting of halogen; hydroxy; amino; lower alkoxycarbonylamino;piperazinyl optionally having one lower alkoxy lower alkyl group;imidazolyl; and morpholinylpiperidyl;

R₂ represents:

(1) hydrogen,

(2) lower alkyl,

(3) lower alkanoyl,

(4) hydroxy lower alkyl,

(5) carboxy;

(6) lower alkoxycarbonyl,

(7) carbamoyl optionally having one or two substituents selected fromthe group consisting of lower alkyl; halogen-substituted lower alkyl;hydroxy lower alkyl; piperazinyl lower alkyl optionally having one loweralkyl group on the piperazine ring; and morpholinyl lower alkyl,(8) carbamoyl lower alkyl optionally having one lower alkyl group on thecarbamoyl group,(9) morpholinyl lower alkyl,(10) piperazinyl lower alkyl optionally having, on the piperazine ring,one substituent selected from the group consisting of lower alkyl andpyridyl optionally having one lower alkyl group,(11) diazepanyl lower alkyl, or(12) amino lower alkyl optionally having, on the amino group, one or twosubstituents selected from the group consisting of lower alkyl,halogen-substituted lower alkyl, hydroxy lower alkyl, and morpholinyllower alkyl;

R₃ represents phenyl, thienyl, furyl, pyrazolyl, or pyrimidinyl,wherein:

the aromatic or heterocyclic ring represented by R₃ may be substitutedwith one or two substituents selected from the group consisting of thefollowing substituents (1) to (14):

(1) lower alkyl,

(2) lower alkoxy,

(3) lower alkanoyl,

(4) halogen,

(5) hydroxy,

(6) hydroxy lower alkyl,

(7) hydroxy lower alkoxy,

(8) protected hydroxy lower alkoxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl lower alkoxy optionally having one lower alkyl group onthe carbamoyl group,

(13) carbamoyl optionally having one morpholinyl lower alkyl group, and

(14) morpholinylpiperidylcarbonyl;

R₄ represents halogen, lower alkyl, or lower alkoxy;

R₅ represents hydrogen or halogen;

R₄ and R₅ may be linked to form a group represented by any of thefollowing formulae:

or a group represented by the following formula:

the group optionally having one or two substituents selected from thegroup consisting of lower alkyl or oxo;

R₆ represents hydrogen or lower alkoxy;

R₇ represents any of the following groups (1) to (11):

(1) hydrogen,

(2) lower alkoxy,

(3) hydroxy lower alkoxy,

(4) protected hydroxy lower alkoxy,

(5) lower alkoxy lower alkoxy,

(6) carbamoyl lower alkoxy optionally having, on the carbamoyl group,one substituent selected from the group consisting of lower alkyl andmorpholinyl lower alkyl,

(7) amino optionally having two substituents selected from the groupconsisting of lower alkyl and cyclo C₃-C₈ alkyl,

(8) cyclo C₃-C₈ alkyloxy,

(9) carboxy lower alkoxy,

(10) lower alkoxycarbonyl lower alkoxy, and

(11) pyrrolidinyl; and

R₆ and R₇ may be linked to form a group represented by any of thefollowing formulae:

Preferred embodiments of various definitions used herein and included inthe scope of the invention are described next.

The term “lower” refers to a group having 1 to 6 carbons (preferably 1to 4 carbons) unless otherwise specified.

Examples of lower alkyl groups include straight or branched C₁₋₆(preferably C₁₋₄) alkyl groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl,3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl, etc.

Examples of lower alkenyl groups include straight or branched C₂₋₆alkenyl groups with 1-3 double bonds, including both trans and cisforms. Examples thereof include vinyl, 1-propenyl, 2-propenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl,3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl,2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl,3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl,1,3-hexadienyl, 1,4-hexadienyl, etc.

Examples of C₃-C₈ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

The C₃-C₈ cycloalkyl moieties of the C₃-C₈ cycloalkyloxy groups are asdescribed above.

Examples of C₃-C₈ cycloalkyl lower alkyl groups include the lower alkylgroups having one to three (preferably one) C₃-C₈ cycloalkyl group(s)described above.

Examples of lower alkoxy groups include straight or branched C₁₋₆(preferably C₁₋₄) alkoxy groups such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy,isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy,etc.

Examples of lower alkoxy lower alkyl groups include the lower alkylgroups having one to three (preferably one) lower alkoxy group(s)described above.

Examples of halogen atoms include fluorine, chlorine, bromine, andiodine.

Examples of halogen-substituted lower alkyl groups include the loweralkyl groups having one to seven halogen atom(s), preferably one tothree halogen atom(s). Examples thereof include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,2-fluoroethyl, 2-bromoethyl, 2-chloroethyl, 3-bromopropyl,3-chloropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl,2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl,2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl,4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl,5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6-trifluorohexyl,6-chlorohexyl, perfluorohexyl, etc.

Examples of halogen-substituted lower alkoxy groups include the loweralkoxy groups having one to seven halogen atom(s), preferably one tothree halogen atom(s). Examples thereof include fluoromethoxy,difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy,3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy,3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy,4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy,2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropentoxy,6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, etc.

Examples of lower alkylthio groups include alkylthio groups wherein thealkyl moiety is the lower alkyl group mentioned above.

Examples of lower alkanoyl groups include straight or branched C₁₋₆(preferably C₁₋₄) alkanoyl groups such as formyl, acetyl, propionyl,butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, etc.

Examples of halogen-substituted lower alkanoyl groups include the loweralkanoyl groups having one to seven halogen atom(s), preferably one tothree halogen atom(s). Examples thereof include fluoroacetyl,difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl,bromoacetyl, dibromoacetyl, 2,2-difluoroethyl, 2,2,2-trifluoropropionyl,pentafluoropropionyl, 3-chlorobutanoyl, 3,3,3-trichlorobutanoyl,4-chlorobutanoyl, etc.

Examples of protected hydroxy groups include the lower alkyl groupsdescribed above, the lower alkanoyl groups described above, phenyl(lower) alkyl groups (such as benzyl, 4-methoxybenzyl, trityl, etc.),tetrahydropyranyl groups, etc.

Examples of hydroxy lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) hydroxy group(s).

Examples of protected hydroxy lower alkyl groups include the lower alkylgroups having one to three (preferably one) protected hydroxy group(s)described above.

Examples of amino lower alkanoyl groups include the lower alkanoylgroups having one to three (preferably one) amino group(s).

Examples of hydroxy lower alkanoyl groups include the lower alkanoylgroups having one to three (preferably one) hydroxy group(s).

Examples of protected hydroxy lower alkanoyl groups include the loweralkanoyl groups having one to three (preferably one) protected hydroxygroup(s) described above.

Examples of phosphonooxy lower alkanoyl groups include the loweralkanoyl groups having one to three (preferably one) protectedphosphonooxy group(s).

The phosphonooxy lower alkanoyl moieties of the phosphonooxy loweralkanoyloxy groups are as described above.

Examples of phosphonooxy lower alkanoyloxy lower alkyl groups includethe lower alkyl groups having one to three (preferably one) phosphonooxylower alkanoyloxy group(s) described above.

Examples of amino lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) amino group(s).

Examples of carboxy lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) carboxy group(s).

Examples of carbamoyl lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) carbamoyl group(s).

Examples of lower alkanoyl lower alkyl groups include the lower alkylgroups having one to three (preferably one) lower alkanoyl group(s).

Examples of lower alkoxy lower alkyl groups include the lower alkylgroups having one to three (preferably one) lower alkoxy group(s).

Examples of phosphonooxy lower alkyl groups include the lower alkylgroups having one to three (preferably one) phosphonooxy group(s).

Examples of lower alkylthio lower alkyl groups include the lower alkylgroups having one to three (preferably one) lower alkylthio group(s)described above.

The lower alkanoyl moieties of the lower alkanoyl amino groups are asdescribed above.

Examples of lower alkanoyl amino lower alkyl groups include the loweralkyl groups having one to three (preferably one) lower alkanoyl aminogroup(s) described above.

The amino lower alkyl moieties of the amino lower alkylthio groups areas described above.

Examples of amino lower alkylthio lower alkyl groups include the loweralkyl groups having one to three (preferably one) amino lower alkylthiogroup(s) described above.

The hydroxy lower alkyl moieties of the hydroxy lower alkylthio groupsare as described above.

Examples of hydroxy lower alkylthio lower alkyl groups include the loweralkyl groups having one to three (preferably one) hydroxy loweralkylthio group(s) described above.

The carboxy lower alkyl moieties of the carboxy lower alkylthio groupsare as described above.

Examples of carboxy lower alkylthio lower alkyl groups include the loweralkyl groups having one to three (preferably one) carboxy loweralkylthio group(s) described above.

The lower alkoxy moieties of the lower alkoxy carbonyl groups are asdescribed above.

The lower alkoxy carbonyl moieties of the lower alkoxy carbonyl aminogroups are as described above.

Examples of lower alkoxy carbonyl lower alkyl groups include the loweralkyl groups having one to three (preferably one) lower alkoxy carbonylgroup(s) described above.

The lower alkoxy carbonyl lower alkyl moieties of the lower alkoxycarbonyl lower alkylthio groups are as described above.

Examples of lower alkoxy carbonyl lower alkylthio lower alkyl groupsinclude the lower alkyl groups having one to three (preferably one)lower alkoxy carbonyl lower alkylthio group(s) described above.

The lower alkyl moieties of the lower alkylthio carbonyl groups are asdescribed above.

The amino lower alkanoyl moieties of the amino lower alkanoyloxy groupsare as described above.

Examples of amino lower alkanoyloxy lower alkyl groups include the loweralkyl groups having one to three (preferably one) amino loweralkanoyloxy group(s).

Examples of amino lower alkylthio carbonyl groups include the loweralkylthio carbonyl groups having one to three (preferably one) aminogroup(s).

Examples of amino lower alkylthio carbonyl lower alkyl groups includethe lower alkyl groups having one to three (preferably one) amino loweralkylthio carbonyl group(s) described above.

Examples of benzoyloxy lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) benzoyloxy group(s).

The hydroxy lower alkyl moieties of the hydroxy lower alkylsulfonylgroups are as described above.

Examples of hydroxy lower alkylsulfonyl lower alkyl groups include thelower alkyl groups having one to three (preferably one) hydroxy loweralkylsulfonyl group(s) described above.

The carboxy lower alkyl moieties of the carboxy lower alkylsulfonylgroups are as described above.

Examples of carboxy lower alkylsulfonyl lower alkyl groups include thelower alkyl groups having one to three (preferably one) carboxy loweralkylsulfonyl group(s) described above.

The lower alkoxy carbonyl lower alkyl moieties of the lower alkoxycarbonyl lower alkylsulfonyl groups are as described above.

Examples of lower alkoxy carbonyl lower alkylsulfonyl lower alkyl groupsinclude the lower alkyl groups having one to three (preferably one)lower alkoxy carbonyl lower alkylsulfonyl group(s) described above.

The lower alkanoyl lower alkyl moieties of the lower alkanoyl loweralkylsulfonyl groups are as described above.

Examples of lower alkanoyl lower alkylsulfonyl lower alkyl groupsinclude the lower alkyl groups having one to three (preferably one)lower alkanoyl lower alkylsulfonyl group(s) described above.

Examples of hydroxy lower alkoxy groups include the lower alkoxy groupshaving one to three (preferably one) hydroxy group(s).

Examples of protected hydroxy lower alkoxy groups include the loweralkoxy groups having one to three (preferably one) protected hydroxygroup(s) described above.

Examples of carboxy lower alkoxy groups include the lower alkoxy groupshaving one to three (preferably one) carboxy group(s).

Examples of lower alkoxy carbonyl lower alkoxy groups include the loweralkoxy groups having one to three (preferably one) lower alkoxy carbonylgroups described above.

Examples of carbamoyl lower alkoxy groups include the lower alkoxygroups having one to three (preferably one) carbamoyl group(s).

Examples of lower alkoxy lower alkoxy groups include the lower alkoxygroups having one to three (preferably one) lower alkoxy group(s)described above.

Examples of piperazinyl lower alkyl groups include the lower alkylgroups having one to three (preferably one) piperazinyl group(s).

Examples of piperazinyl lower alkylsulfonyl lower alkyl groups includethe lower alkyl groups having one to three (preferably one) piperazinyllower alkylsulfonyl group(s) wherein the piperazinyl lower alkylmoieties are as described above.

Examples of piperazinyl carbonyl lower alkylsulfonyl groups include thelower alkylsulfonyl groups having one to three (preferably one)piperazinyl carbonyl group(s).

Examples of piperazinyl carbonyl lower alkylsulfonyl lower alkyl groupsinclude the lower alkyl groups having one to three (preferably one)piperazinyl carbonyl lower alkylsulfonyl group(s) described above.

Examples of piperazinyl lower alkoxy carbonyl groups include the loweralkoxy carbonyl groups having one to three (preferably one) piperazinylgroup(s).

Examples of piperazinyl lower alkoxy carbonyl lower alkyl groups includethe lower alkyl groups having one to three (preferably one) piperazinyllower alkoxy carbonyl group(s).

Examples of morpholinyl lower alkyl groups include the lower alkylgroups having one to three (preferably one) morpholinyl group(s).

Examples of oxazepanyl lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) oxazepanyl group(s).

Examples of piperidyl lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) piperidyl group(s).

Examples of azetidyl lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) azetidyl group(s).

Examples of isoindolyl lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) isoindolyl group(s).

Examples of diazepanyl lower alkyl groups include the lower alkyl groupshaving one to three (preferably one) diazepanyl group(s).

The process of producing the compound of the invention is describedbelow in detail.

The quinolone compound represented by General Formula (1) (hereinafteralso referred to as Compound (1)) can be produced by various methods;for example, by a method according to the following Reaction Scheme 1 or2.

wherein R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, and X₁represents a halogen atom.

Examples of halogen atoms represented by X₁ include fluorine, chlorine,bromine, and iodine.

Preferable leaving groups in the reaction include halogens. Among these,iodine is particularly preferable.

Compound (1) can be produced by the reaction of the compound representedby General Formula (2) with the compound represented by General Formula(3) in an inert solvent or without using any solvents, in the presenceor absence of a basic compound, in the presence of a palladium catalyst.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbons such as benzene, toluene, and xylene; lower alcohols suchas methanol, ethanol, and isopropanol; ketones such as acetone andmethyl ethyl ketone; and polar solvents such as N,N-dimethylformamide(DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile. These inert solvents can be used singly or in combinationsof two or more.

Palladium compounds used in the reaction are not particularly limited,but include, for example, tetravalent palladium catalysts such as sodiumhexachloropalladiumate(IV) tetrahydrate and potassiumhexachloropalladiumate(IV); divalent palladium catalysts such aspalladium(II) chloride, palladium(II) bromide, palladium(II) acetate,palladium(II) acetylacetonato, dichlorobis(benzonitrile)palladium(II),dichlorobis(acetonitrile)palladium(II),dichlorobis(triphenylphosphine)palladium(II),dichlorotetraamminepalladium(II),dichloro(cycloocta-1,5-diene)palladium(II), palladium(II)trifluoroacetate, and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II)-dichloromethane complex; zerovalent palladiumcatalysts such as tris(dibenzylideneacetone)2 palladium(0),tris(dibenzylideneacetone)2 palladium(0) chloroform complex, andtetrakis(triphenylphosphine)palladium(0), etc. These palladium compoundsare used singly or in combinations of two or more.

In the reaction, the amount of the palladium catalyst is notparticularly limited, but is typically in the range from 0.000001 to 20moles in terms of palladium relative to 1 mol of the compound of GeneralFormula (2). The amount of the palladium catalyst is preferably in therange from 0.0001 to 5 moles in terms of palladium relative to 1 mol ofthe compound of General Formula (2).

This reaction advantageously proceeds in the presence of a suitableligand. Examples of ligands of the palladium catalyst include2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP),tri-o-tolylphosphine, bis(diphenylphosphino)ferrocene,triphenylphosphine, tri-t-butylphosphine, and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS). Theseligands are used singly or in combinations of two or more.

The proportion of the palladium catalyst and ligand is not particularlylimited. The amount of the ligand is about 0.1 to about 100 moles,preferably about 0.5 to about 15 moles, per mole of the palladiumcatalyst.

Various known inorganic and organic bases can be used as basiccompounds.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogencarbonates such as lithium hydrogencarbonate, sodiumhydrogencarbonate, and potassium hydrogencarbonate; alkali metals suchas sodium and potassium; phosphates such as sodium phosphate andpotassium phosphate; amides such as sodium amide; and alkali metalhydrides such as sodium hydride and potassium hydride.

Organic bases include, for example, alkali metal lower alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide, and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includealkali metal carbonates such as sodium carbonate, potassium carbonate,cesium carbonate, and lithium carbonate.

A basic compound is usually used in an amount of 0.5 to 10 moles,preferably 0.5 to 6 moles, per mole of the compound of General Formula(2).

In the above Reaction Scheme 1, the compound of General Formula (3) isusually used in an amount of at least about 1 mole, preferably about 1to about 5 moles, per mole of the compound of General Formula (2).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours. The reaction is also achieved by heating at100 to 200° C. for 5 minutes to 1 hour using a microwave reactor.

The compound represented by General Formula (3), which is used as astarting material in Reaction Scheme 1 is an easily available knowncompound. The compound represented by General Formula (2) includes anovel compound, and the compound is produced in accordance with ReactionScheme 6 shown below.

wherein R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, and R₈represents a lower alkoxy group.

The lower alkoxy group represented by R₈ in General Formula (5) has thesame definition as described above.

The compound represented by General Formulae (4) is reacted with thecompound represented by General Formula (5) in an inert solvent orwithout using any solvents, in the presence or absence of an acidcatalyst, thereby giving an intermediate compound represented by GeneralFormula (6). Then, the resulting compound is cyclized to produce thecompound represented by General Formula (1).

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbons such as benzene, toluene, and xylene; lower alcohols suchas methanol, ethanol, and isopropanol; and polar solvents such asN,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide, and acetonitrile. These inert solventscan be used singly or in combinations of two or more.

Various kinds of known acid catalysts can be used, includingtoluenesulfonic acid, methanesulfonic acid, xylene sulfonic acid,sulfuric acid, glacial acetic acid, boron trifluoride, acidic ionexchangers, etc. These acid catalysts can be used singly or incombinations of two or more.

Among such acids, acidic ion exchangers are preferably used. Examples ofacidic ion exchangers include polymeric cation exchangers available fromthe market such as Lewatit S100, Zeo-karb 225, Dowex 50, AmberliteIR120, or Amberlyst 15 and like styrene sulfonic acid polymers; LewatitPN, Zeo-karb 215 or 315, and like polysulfonic acid condensates; LewatitCNO, Duolite CS100, and like m-phenolic carboxylic acid resins; orPermutit C, Zeo-karb 226 or Amberlite IRC 50, and like polyacrylates. Ofthese, Amberlyst 15 is particularly preferred.

An acid catalyst is usually used in an amount of 0.0001 to 100 moles,preferably 0.5 to 6 moles, per mole of the compound of General Formula(4).

In Reaction Scheme 2, the compound of General Formula (5) is usuallyused in an amount of at least about 1 mole, preferably about 1 to about5 moles, per mole of the compound of General Formula (4).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C. During the reaction,azeotropic removal of water is conducted until the reaction watergeneration is completed. The reaction is usually finished in about 1 toabout 30 hours.

The process of producing the compound of General Formula (1) via acyclization reaction of the intermediate compound represented by GeneralFormula (6) can be carried out by heating the compound in a solvent suchas diphenyl ether, or by heating the compound in the absence of asolvent. The reaction is conducted at 150 to 300° C. for 5 minutes to 2hours.

The compound represented by General Formula (4), used as a startingmaterial in Reaction Scheme 2 described above is a known compound or canbe produced easily using a known compound. The compound represented byGeneral Formula (5) includes a novel compound, and the compound ismanufactured in accordance with, for example, the methods shown inReaction Scheme 4 and Reaction Scheme 5 described below.

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, and R₁′ is agroup represented by R₁ other than hydrogen, and X₂ represents a groupthat undergoes the same substitution reaction as that of a halogen or ahalogen atom.

Halogens represented by X₂ in General Formula (7) include the halogenatom described above. Groups that undergo the same substitution reactionas that of the halogen atoms represented by X₂ include lower alkanesulfonyloxy groups, aryl sulfonyloxy groups, aralkyl sulfonyloxy groups,etc.

Examples of lower alkane sulfonyloxy groups include straight or branchedC₁₋₆ alkane sulfonyloxy groups, such as methane sulfonyloxy, ethanesulfonyloxy, n-propane sulfonyloxy, isopropane sulfonyloxy, n-butanesulfonyloxy, tert-butane sulfonyloxy, n-pentane sulfonyloxy, andn-hexane sulfonyloxy.

Examples of aryl sulfonyloxy groups include naphthyl sulfonyloxy andphenyl sulfonyloxy optionally substituted on a phenyl ring with one tothree substituent(s) selected from the group consisting of straight orbranched C₁₋₆ alkyl groups, straight or branched C₁₋₆ alkoxy groups,nitro groups, and halogen atoms as a substituent(s). Examples of phenylsulfonyloxy groups optionally substituted with the above substituent(s)include phenyl sulfonyloxy, 4-methylphenyl sulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenyl sulfonyloxy, 4-methoxyphenyl sulfonyloxy,2-nitrophenyl sulfonyloxy, 3-chlorophenyl sulfonyloxy, etc. Examples ofnaphthyl sulfonyloxy groups include α-naphthyl sulfonyloxy, β-naphthylsulfonyloxy, etc.

Examples of aralkyl sulfonyloxy groups include phenyl-substitutedstraight or branched C₁₋₆ alkane sulfonyloxy groups that may have, onthe phenyl ring, one to three substituent(s) selected from the groupconsisting of straight or branched C₁₋₆ alkyl groups, straight orbranched C₁₋₆ alkoxy groups, a nitro group and halogen atoms as asubstituent(s); and naphtyl-substituted straight or branched C₁₋₆ alkanesulfonyloxy groups. Examples of alkane sulfonyloxy groups substitutedwith the above-mentioned phenyl group(s) include benzyl sulfonyloxy,2-phenylethyl sulfonyloxy, 4-phenylbutyl sulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzyl sulfonyloxy, 4-nitrobenzyl sulfonyloxy,4-methoxybenzyl sulfonyloxy, 3-chlorobenzyl sulfonyloxy, etc. Examplesof alkane sulfonyloxy groups substituted with the above-mentionednaphthyl group(s) include α-naphthylmethyl sulfonyloxy, β-naphthylmethylsulfonyloxy, etc.

The compound represented by General Formula (1b) can be produced by thereaction of the compound represented by General Formula (1a) with thecompound represented by General Formula (7) in an inert solvent orwithout using any solvents, in the presence or absence of a basiccompound.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbons such as benzene, toluene, and xylene; lower alcohols suchas methanol, ethanol, and isopropanol; ketones such as acetone andmethyl ethyl ketone; and polar solvents such as N,N-dimethylformamide(DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile. These inert solvents can be used singly or in combinationsof two or more.

As a basic compound, various known inorganic bases and organic bases canbe used.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogencarbonate, and potassium hydrogen carbonate; alkali metals such assodium and potassium; amides such as sodium amide; and alkali metalhydrides such as sodium hydride and potassium hydride.

Organic bases include, for example, alkali metal lower alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide; and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyl diisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includeinorganic bases such as sodium hydride and potassium hydride.

A basic compound is usually used in an amount of 0.5 to 10 moles,preferably 0.5 to 6 moles, per mole of the compound of General Formula(1a).

In Reaction Scheme 1, the compound of General Formula (7) is usuallyused in an amount of at least about 1 mole, preferably 1 to about 5moles, per mole of the compound of General Formula (1a).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at 0° C. to 200° C., and preferably atroom temperature to 150° C., and is usually completed in about 1 toabout 30 hours.

The compound represented by General Formula (7), which is used as astarting material in Reaction Scheme 3 is an easily available knowncompound.

Compound (5) and Compound (2), which are the starting materials of thecompound of the invention, include novel compounds, and can be producedby various methods; for example, by methods according to the followingReaction Schemes 4 to 6.

wherein R₂, R₃, and R₈ are as defined above, and R₉ represents a loweralkoxy group.

The lower alkoxy group represented by R₉ in General Formula (9) has thesame definition as described above.

The compound represented by General Formula (5) can be produced by thereaction of the compound represented by General Formula (8) with thecompound represented by General Formula (9) in an inert solvent orwithout using any solvents, in the presence or absence of a basiccompound.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbons such as benzene, toluene, and xylene; lower alcohols suchas methanol, ethanol, and isopropanol; ketones such as acetone andmethyl ethyl ketone; and polar solvents such as N,N-dimethylformamide(DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile. These inert solvents can be used singly or in combinationsof two or more.

As a basic compound, various known inorganic bases and organic bases canbe used.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogencarbonates such as lithium hydrogencarbonate, sodiumhydrogencarbonate, and potassium hydrogencarbonate; alkali metals suchas sodium and potassium; amides such as sodium amide; and alkali metalhydrides such as sodium hydride and potassium hydride.

Organic bases include, for example, alkali metal lower alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide; and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

These basic compounds are used singly or in combinations of two or more.More preferable examples of basic compounds used in the reaction includeinorganic bases such as sodium hydroxide, potassium hydroxide, etc.

A basic compound is usually used in an amount of about 1 to about 10moles, preferably about 1 to about 6 moles, per mole of the compound ofGeneral Formula (8).

In Reaction Scheme 4, the compound of General Formula (9) is usuallyused in an amount of at least about 1 mole, preferably about 1 to about5 moles, per mole of the compound of General Formula (8).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The compounds represented by General Formulae (8) and (9), which areused as starting materials in Reaction Scheme 4, are easily availableknown compounds.

wherein R₂, R₃, and R₈ are as defined above, and X₃ represents a halogenatom.

The halogen atom represented by X₃ in General Formula (9′) has the samedefinition as described above.

The compound represented by General Formula (5) can be produced by thereaction of the compound represented by General Formula (8′) with thecompound represented by General Formula (9′) in an inert solvent orwithout using any solvents, in the presence of a basic compound such ascesium carbonate and a copper catalyst such as copper iodide.

Preferable examples of inert solvents include polar solvents such asN,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide, and acetonitrile. These inert solventscan be used singly or in combinations of two or more.

The reaction may be conducted in the presence of amino acids such asL-proline.

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The compounds represented by General Formulae (8′) and (9′) used asstarting materials in Reaction Scheme 5 described above are knowncompounds, or can be produced easily using known compounds.

wherein R₄, R₅, R₆, and R₇ are as defined above, and X_(1a) represents ahalogen atom. R₁₀ represents a lower alkyl group.

The lower alkyl group represented by R₁₀ and a halogen atom representedby X_(1a) have the same definitions as described above.

The compound represented by General Formula (12) can be produced by thecondensation reaction of the compounds represented by General Formulae(4), (10), and (11) in an inert solvent or without using any solvents.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, and ethylene glycol dimethyl ether; halogenatedhydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane,and carbon tetrachloride; aromatic hydrocarbons such as benzene,toluene, and xylene; lower alcohols such as methanol, ethanol, andisopropanol; and polar solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile. The compound represented by General Formula (11) can beused as a solvent in place of the solvents mentioned above. These inertsolvents can be used singly or in combinations of two or more.

In Reaction Scheme 6, the compound of General Formula (10) is usuallyused in an amount of at least 1 mole, preferably about 1 to about 5moles, per mole of the compound of General Formula (4).

The compound represented by General Formula (11) is used in an amountexceeding that of the compound of General Formula (10).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The compound represented by General Formula (13) can be produced by thecyclization reaction of the compound represented by General Formula (12)in an inert solvent or without using any solvents.

Examples of inert solvents include ethers such as diphenyl ether.

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 300° C., andpreferably at 150 to 300° C., and is usually completed in about 1 toabout 30 hours.

The compound represented by General Formula (2a) can be produced by thereaction of the compound represented by General Formula (13) with thecompound represented by General Formula (14) in an inert solvent orwithout using any solvents, in the presence or absence of a basiccompound.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycoldimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbons such as benzene, toluene, and xylene; lower alcohols suchas methanol, ethanol, and isopropanol; ketones such as acetone andmethyl ethyl ketone; polar solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile. These inert solvents can be used singly or in combinationsof two or more.

As a basic compound, various known inorganic bases and organic bases canbe used.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogencarbonates such as lithium hydrogencarbonate, sodiumhydrogencarbonate, and potassium hydrogencarbonate; alkali metals suchas sodium and potassium; amides such as sodium amide; and alkali metalhydrides such as sodium hydride and potassium hydride.

Organic bases include, for example, alkali metal alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide; and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includealkali metal carbonates such as sodium carbonate, potassium carbonate,cesium carbonate, and lithium carbonate, etc.

A basic compound is usually used in an amount of 0.5 to 10 moles,preferably 0.5 to 6 moles, per mole of the compound of General Formula(13).

In Reaction Scheme 6, the compound of General Formula (14) is usuallyused in an amount of at least 0.5 moles, preferably about 0.5 to about 5moles, per mole of the compound of General Formula (13).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The compounds represented by General Formulae (10), (11) and (14), whichare used as starting materials in Reaction Scheme 6, are easilyavailable known compounds.

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above; R₁a representsa phosphonooxy lower alkyl group having one or more hydroxy-protectinggroups, a phosphonooxy lower alkanoyloxy lower alkyl group having one ormore hydroxy-protecting groups, or a benzoyloxy lower alkyl group havingone or more phosphonooxy groups substituted with one or morehydroxy-protecting groups on the benzene ring; and R₁b represents aphosphonooxy lower alkyl group, a phosphonooxy lower alkanoyloxy loweralkyl group, or a benzoyloxy lower alkyl group having one or morephosphonooxy groups on the benzene ring.

Compound (1d) can be produced by the deprotection of thehydroxy-protecting group from Compound (1c) in an inert solvent orwithout using any solvents.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, and ethylene glycol dimethyl ether; halogenatedhydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane,and carbon tetrachloride; aromatic hydrocarbons such as benzene,toluene, and xylene; lower alcohols such as methanol, ethanol, andisopropanol; and polar solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile. The compound represented by General Formula (1c) may alsobe used as a solvent instead of the above solvents. These inert solventscan be used singly or in combinations of two or more.

This reaction is carried out by a conventional method such as hydrolysisor reduction.

Hydrolysis is carried out preferably in the presence of bases or acidsincluding a Lewis acid.

Suitable examples of bases include inorganic bases such as alkali metalhydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali earthmetal hydroxides (e.g., magnesium hydroxide, calcium hydroxide), alkalimetal carbonates (e.g., sodium carbonate, potassium carbonate), alkaliearth metal carbonates (e.g., magnesium carbonate, calcium carbonate),alkali metal hydrogencarbonates (e.g., sodium hydrogencarbonate,potassium hydrogencarbonate); and organic bases such as trialkyl amines(e.g., trimethylamine, triethylamine), picoline,1,5-diazabicyclo[4.3.0]non-5-en, and 1,4-diazabicyclo[2.2.2]octane, and1,8-diazabicyclo[5.4.0]undeca-7-en.

Examples of suitable acids include organic acids (e.g., formic acid,acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid)and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid). Deprotection using Lewis acids such as trihaloacetic acids (e.g.,trichloroacetic acid, trifluoroacetic acid) is carried out preferably inthe presence of a cation scavenger (e.g., anisole, phenol). In thereaction, a liquid base or acid can also be used as a solvent.

The reaction temperature is not limited, and the reaction is usuallycarried out under cooling or warming.

Reduction methods applicable to the elimination reaction includechemical reduction and catalytic reduction.

Suitable reducing agents for use in chemical reduction are a combinationof a metal (e.g., tin, zinc, iron) or metallic compound (e.g., chromiumchloride, chromium acetate) and an organic or inorganic acid (e.g.formic acid, acetic acid, propionic acid, trifluoroacetic acid,p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid).

Suitable catalysts for use in catalytic reduction are conventional onessuch as platinum catalysts (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire),palladium catalysts (e.g. spongy palladium, palladium black, palladiumoxide, palladium-carbon, colloidal palladium, palladium-barium sulfate,palladium-barium carbonate), nickel catalysts (e.g. reduced nickel,nickel oxide, Raney nickel), cobalt catalysts (e.g. reduced cobalt,Raney cobalt), iron catalysts (e.g. reduced iron, Raney iron), coppercatalysts (e.g. reduced copper, Raney copper, Ullman copper), and thelike.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction, such as water; an alcohol such asmethanol, ethanol, trifluoroethanol, or ethyleneglycol; an ether such asacetone, diethylether, dioxane, or tetrahydrofuran; a halogenatedhydrocarbon such as chloroform, methylene chloride, or ethylenechloride; an ester such as methyl acetate or ethyl acetate;acetonitrile; N,N-dimethylformamide; pyridine; any other organicsolvent; or a mixture of these solvents. The reaction usually proceedsat room temperature to 200° C., and preferably at room temperature to150° C., and is usually completed in about 1 to about 30 hours.

Further, the conditions for the deprotection reaction of thehydroxy-protecting group are not limited to the reaction conditionsdescribed above. For example, reactions described by T. W. Green and P.G. M. Wuts (Protective Groups in Organic Synthesis, 4th edition) andJohn Wiley & Sons (New York, 1991, P. 309) can also be applied to thereaction process.

The raw material compounds used in each of the reaction schemesdescribed above may include suitable salts, and the objective compoundsobtained via each of the reactions may form suitable salts. Thesepreferable salts include the following preferable salts of Compound (1).

Suitable salts of Compound (1) are pharmacologically allowable saltsincluding, for example, salts of inorganic bases such as metal saltsincluding alkali metal salts (e.g., sodium salts, potassium salts, etc.)and alkaline earth metal salts (e.g., calcium salts, magnesium salts,etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate,potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkalimetal hydrogencarbonates (e.g., lithium hydrogencarbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), and alkali metalhydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, cesium hydroxide, etc.); salts of organic bases such astri(lower)alkylamine (e.g., trimethylamine, triethylamine,N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine,imidazole, picoline, dimethylaminopyridine, dimethylaniline,N-(lower)alkyl-morpholine (e.g., N-methylmorpholine, etc.),1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and trishydroxymethyl amino methane; inorganic acid salts suchas hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, andphosphate; and organic acid salts such as formate, acetate, propionate,oxalate, malonate, succinate, fumarate, maleate, lactate, malate,citrate, tartrate, carbonate, picrate, methanesulfonate,ethanesulfonate, p-toluenesulfonate, and glutamate.

In addition, compounds in a form in which a solvate (for example,hydrate, ethanolate, etc.) was added to the starting materials and theobjective compound shown in each of the reaction schemes are alsoincluded in each of the general formulae. Hydrate can be mentioned as apreferable solvate.

Each of the objective compounds obtained according to the above reactionschemes can be isolated and purified from the reaction mixture by, forexample, cooling the reaction mixture first, performing an isolationprocedure such as filtration, concentration, extraction, etc., toseparate a crude reaction product, and then subjecting the crudereaction product to a usual purification procedure such as columnchromatography, recrystallization, etc.

The compound represented by General Formula (1) according to the presentinvention naturally includes geometrical isomers, stereoisomers, opticalisomers, and like isomers.

The following points should be noted regarding the compound of GeneralFormula (1) shown above. Specifically, when R₁ of General Formula (1)represents a hydrogen atom, the compound includes a tautomer of thequinolone ring. That is, in the quinolone compound of General Formula(1), when R₁ represents a hydrogen atom (1′),

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, the compound ofthe tautomer can be represented by Formula (1″),

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above. That is, bothof the compounds represented by Formulae (1′) and (1″) are in thetautomeric equilibrium state represented by the following balanceformula.

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above.

Such tautomerism between a 4-quinolone compound and a 4-hydroxyquinolinecompound is technically known, and it is obvious for a person skilled inthe art that both of the above-described tautomers are balanced andmutually exchangeable.

Therefore, the compound represented by General Formula (1) of thepresent invention naturally includes the tautomers as mentioned above.

In the specification, the constitutional formula of a 4-quinolonecompound is suitably used as a constitutional formula of the objectiveor starting material including compounds of such tautomers.

The present invention also includes isotopically labeled compounds thatare identical to the compounds represented by Formula (1), except thatone or more atoms are replaced by one or more atoms having specificatomic mass or mass numbers. Examples of isotopes that can beincorporated into the compounds of the present invention includehydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, suchas ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F, and ³⁶Cl. Certain isotopicallylabeled compounds of the present invention, which include theabove-described isotopes and/or other isotopes of other atoms, forexample, those into which radioisotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassay. Tritiated (i.e., ³H), and carbon-14 (i.e., ¹⁴C) isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)can afford certain therapeutic advantages resulting from greatermetabolic stability, for example, an increased in vivo half-life orreduced dosage requirements. The isotopically labeled compounds of thepresent invention can generally be prepared by substituting a readilyavailable, isotopically labeled reagent for a non-isotopically labeledreagent according to the method disclosed in the schemes above and/or inthe Examples below.

The compound of General Formula (1) and the salt thereof are used in theform of general pharmaceutical preparations. The preparations areobtained using typically employed diluents or excipients such asfillers, extenders, binders, wetting agents, disintegrators,surfactants, lubricants, etc. The form of such pharmaceuticalpreparations can be selected according to the purpose of the therapy.Typical examples include tablets, pills, powders, solutions,suspensions, emulsions, granules, capsules, suppositories, injections(solutions, suspensions, etc.), and the like.

To form tablets, any of various carriers conventionally known in thisfield can be used. Examples thereof include lactose, white sugar, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose, silicic acid, and other excipients; water, ethanol, propanol,simple syrup, glucose solutions, starch solutions, gelatin solutions,carboxymethylcellulose, shellac, methylcellulose, potassium phosphate,polyvinylpyrrolidone and other binders; dry starch, sodium alginate,agar powder, laminarin powder, sodium hydrogen carbonate, calciumcarbonate, fatty acid esters of polyoxyethylene sorbitan, sodium laurylsulfate, stearic acid monoglycerides, starch, lactose and otherdisintegrators; white sugar, stearin, cacao butter, hydrogenated oilsand other disintegration inhibitors; quaternary ammonium bases, sodiumlauryl sulfate and other absorption promoters; glycerol, starch andother wetting agents; starch, lactose, kaolin, bentonite, colloidalsilicic acid and other adsorbents; purified talc, stearates, boric acidpowder, polyethylene glycol and other lubricants; etc. Further, suchtablets may be coated with typical coating materials as required, toprepare, for example, sugar-coated tablets, gelatin-coated tablets,enteric-coated tablets, film-coated tablets, double- or multi-layeredtablets, etc.

To form pills, any of various carriers conventionally known in thisfield can be used. Examples thereof include glucose, lactose, starch,cacao butter, hydrogenated vegetable oils, kaolin, talc and otherexcipients; gum arabic powder, tragacanth powder, gelatin, ethanol andother binders; laminarin, agar and other disintegrators; etc.

To form suppositories, any of various carriers conventionally known inthis field can be used. Examples thereof include polyethylene glycol,cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.

Capsules can be prepared by mixing the active principal compound withthe above-mentioned carriers to enclose the former in a hard gelatincapsule, soft gelatin capsule or the like.

To form an injection, a solution, emulsion or suspension is sterilizedand preferably made isotonic to blood. Any of the diluents widely usedfor such forms in this field can be employed to form the injection.Examples of such diluents include water, ethyl alcohol, macrogol,propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan, etc.

In this case, the pharmaceutical preparation may contain sodiumchloride, glucose or glycerol in an amount sufficient to prepare anisotonic solution, and may contain typical solubilizers, buffers,analgesic agents, etc. Further, if necessary, the pharmaceuticalpreparation may contain coloring agents, preservatives, flavors,sweetening agents, etc., and/or other medicines.

The amount of the compound represented by the General Formula (1) andthe salt thereof included in the pharmaceutical preparation of thepresent invention is not limited, and can be suitably selected from awide range. The proportion is generally about 0.1 to about 70 wt. %,preferably about 0.1 to about 30 wt. % of the pharmaceuticalpreparation.

The route of administration of the pharmaceutical preparation of thepresent invention is not particularly limited, and the preparation isadministered by a route suitable to the form of the preparation,patient's age, sex and other conditions, and severity of the disease.For example, tablets, pills, solutions, suspensions, emulsions, granulesand capsules are administered orally. Injections are intravenouslyadministered singly or as mixed with typical injection transfusions suchas glucose solutions, amino acid solutions or the like, or singlyadministered intramuscularly, intracutaneously, subcutaneously orintraperitoneally, as required. Suppositories are administeredintrarectally.

The dosage of the pharmaceutical preparation of the invention issuitably selected according to the method of use, patient's age, sex andother conditions, and severity of the disease. The amount of activeprincipal compound is usually about 0.1 to about 10 mg/kg bodyweight/day. Further, it is desirable that the pharmaceutical preparationin each unit of the administration form contains the active principalcompound in an amount of about 1 to about 200 mg.

The use of the compound of the present invention in combination withL-dopa preparations, dopamine receptor agonists, dopamine metabolismenzyme inhibitors, dopamine release-rate-promoting preparations, centralanticholinergic agents, and the like can achieve effects such as dosagereduction, improvement of side effects, increased therapeutic efficacy,etc., which were not attained by known therapies.

Advantageous Effect of Invention

The compounds of the invention protect and improve mitochondrialfunction, and/or protect neurons and repair neuronal function, and henceare effective in the treatment or prevention of neurodegenerativediseases, diseases induced by neurological dysfunction, and diseasesinduced by deterioration of mitochondrial function.

Examples of neurodegenerative diseases include Parkinson's disease,Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration,progressive supranuclear palsy, pure akinesia, Alzheimer's disease,Pick's disease, prion disease, corticobasal degeneration, diffuse Lewybody disease, Huntington's disease, chorea-acanthocytosis, benignhereditary chorea, paroxysmal choreoathetosis, essential tremor,essential myoclonus, Gilles de la Tourette's syndrome, Rett's syndrome,degenerative ballism, dystonia musculorum deformance, athetosis,spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease,Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy,pallidal atrophy, spino-cerebellar degeneration, cerebral corticalatrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy,hereditary olivopontocerebellar atrophy, Joseph disease,dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinkerdisease, Friedreich's Ataxia, Roussy-Levy syndrome, May-White syndrome,congenital cerebellar ataxia, hereditary episodic ataxia, ataxiatelangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy,spinal progressive muscular atrophy, spinobulbar muscular atrophy,Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spasticparaparesis, syringomyelia, syringobulbia, Arnold-Chiari malformation,Stiffman syndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lowermyelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larssonsyndrome, radiation myelopathy, age-related macular degeneration, andcerebral apoplexy (e.g., cerebral infarction and cerebral hemorrhage)and/or dysfunction or neurologic deficits associated with cerebralapoplexy.

Examples of diseases induced by neurological dysfunction include spinalcord injury, chemotherapy-induced neuropathy, diabetic neuropathy,radiation damage, and demyelinating diseases (e.g., multiple sclerosis,acute disseminated encephalomyelitis, transverse myelitis, progressivemultifocal leucoencephalopathy, subacute sclerosing panencephalitis,chronic inflammatory demyelinating polyneuropathy and Guillain-Barresyndrome).

Examples of diseases induced by deterioration of mitochondrial functioninclude Pearson's syndrome, diabetes, deafness, malignant migraine,Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, puremyopathy, mitochondrial cardiomyopathy, myopathy, dementia,gastrointestinal ataxia, acquired sideroblastic anemia,aminoglycoside-induced hearing loss, complex III deficiency due toinherited variants of cytochrome b, multiple symmetrical lipomatosis,ataxia, myoclonus, retinopathy, MNGIE, ANTI disease, Twinkle disease,POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex Ideficiency, complex II deficiency, optic nerve atrophy, fatal infantilecomplex IV deficiency, mitochondrial DNA deficiency, mitochondrial DNAdeficiency syndrome, Leigh's encephalomyelopathy,chronic-progressive-external-ophthalmoplegia syndrome (CPEO),Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria,drug-induced mitochondrial diseases, schizophrenia, major depressiondisorder, bipolar I disorder, bipolar II disorder, mixed episode,dysthymic disorders, atypical depression, seasonal affective disorders,postpartum depression, minor depression, recurrent brief depressivedisorder, intractable depression/chronic depression, double depressionand acute renal failure.

Furthermore, the compound of the invention is effective in theprevention or treatment of diseases such as ischemic heart diseases(e.g., myocardial infarction and/or associated dysfunction, arrhythmia,angina pectoris, occlusion after PTCA, etc.) and/or associateddysfunction, cardiac failure, myocardosis, aortic dissection,immunodeficiency, autoimmune diseases, pancreatic insufficiency,diabetes, atheroembolic renal disease, polycytic kidney disease,medullary cystic disease, renal cortical necrosis, malignantnephrosclerosis, renal failure, hepatic encephalopathy, liver failure,chronic obstructive pulmonary disease, pulmonary embolism,bronchiectasis, silicosis, black lung, idiopathic pulmonary fibrosis,Stevens-Johnson syndrome, toxic epidermal necrolysis, musculardystrophy, clostridial muscle necrosis, and femoral condyle necrosis.

The compound of the invention can achieve effects heretofore unattainedby known therapies, such as reduced dose, reduced side effects, andpotentiated therapeutic effects, when it is administered in combinationwith L-dopa preparations, dopamine receptor agonists, dopaminemetabolism enzyme inhibitors, dopamine release-rate-promotingpreparations, central anticholinergic agents, cholinesterase inhibitors,N-methyl-D-aspartate glutamate receptor antagonists, or other agentsused in thrombolytic therapy, cerebral edema therapy, brain protectiontherapy, antithrombotic therapy, and blood plasma dilution therapy.

Some of Compounds (1) of the invention or salts thereof exhibitremarkably high solubility in, for example, water.

Particularly Compound (1d) or a salt thereof exhibits remarkably highsolubility in, for example, water.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention is described in more detail withreference to Reference Examples, Examples and Pharmacological TestExamples.

Reference Example 1

Production of N-(3-hydroxynaphthalen-2-yl)acetamide

An acetone solution (60 ml) of 3-amino-2-naphthol (5.0 g, 31.4 mmol) wasadded to an aqueous solution (20 ml) of sodium carbonate (4.77 g, 34.5mmol). The mixture was cooled in an ice-water bath, and then acetylchloride (2.27 ml, 32.0 mmol) was added to the mixture dropwise over 5minutes. The resulting mixture was stirred at 0° C. for 4 hours and thenallowed to stand at room temperature overnight. 2N Hydrochloric acid wasadded to the reaction mixture to adjust its pH to 3. The generatedinsoluble matter was separated, washed with water, and then dried,giving a white powder of N-(3-hydroxynaphthalen-2-yl)acetamide (4.9 g,yield: 78%).

Reference Example 2

Production of N-(3-propoxynaphthalen-2-yl)acetamide

N-(3-Hydroxynaphthalen-2-yl)acetamide (4.87 g, 24.2 mmol) was suspendedin acetonitrile (50 ml). A 1-iodopropane (4.52 g, 26.6 mmol)acetonitrile solution (40 ml) and potassium carbonate (4.35 g, 31.5mmol) were added thereto, and the resulting mixture was stirred for 3hours while heating under reflux. The mixture was then cooled to roomtemperature and concentrated to dryness under reduced pressure. Waterwas added to the residue, followed by extraction using dichloromethane.The thus-obtained organic layer was concentrated to dryness underreduced pressure, and the residue was then purified using silica gelcolumn chromatography (dichloromethane:ethyl acetate=20:1). The purifiedproduct was concentrated to dryness under reduced pressure, giving awhite powder of N-(3-propoxynaphthalen-2-yl)acetamide (5.64 g, yield:96%).

Reference Example 3

Production of 3-propoxynaphthalen-2-ylamine

N-(3-Propoxynaphthalen-2-yl)acetamide (2.5 g, 10.2 mmol) was dissolvedin ethanol (10 ml). Concentrated hydrochloric acid (5.2 ml) was addedthereto, and the resulting mixture was stirred for 4 hours while heatingunder reflux. The reaction mixture was cooled to room temperature, and a5N aqueous sodium hydroxide solution (12.5 ml) was added thereto toadjust its pH to 11, followed by extraction using dichloromethane. Thethus-obtained organic layer was concentrated to dryness under reducedpressure, and the residue was then purified using silica gel columnchromatography (dichloromethane). The purified product was concentratedto dryness under reduced pressure, giving a white powder of3-propoxynaphthalen-2-ylamine (2.05 g, yield: 100%).

Reference Example 4

Production of2,2-dimethyl-5-[(3-propoxynaphthalen-2-ylamino)methylene][1,3]dioxane-4,6-dione

Meldrum's acid (2.59 g, 17.9 mmol) was added to methyl orthoformate (16ml), and the mixture was stirred for 2 hours while heating under reflux.3-Propoxynaphthalen-2-ylamine (2.5 g, 12.4 mmol) was added thereto, andthe resulting mixture was stirred for 4 hours while heating underreflux. The reaction mixture was cooled to room temperature and thenconcentrated to dryness under reduced pressure to recrystallize theresidue from methanol, giving a pale brown powder of2,2-dimethyl-5-[(3-propoxynaphthalen-2-ylamino)methylene][1,3]dioxane-4,6-dione (4.19 g, yield: 95%).

Reference Example 5

Production of 5-propoxy-4H-benzo[f]quinolin-1-one

2,2-Dimethyl-5-[(3-propoxynaphthalen-2-ylamino)methylene][1,3]dioxane-4,6-dione (4.19 g, 11.7 mmol) was added todiphenyl ether (15 ml), and the mixture was heated with a mantle heaterand then maintained under reflux for 2 hours. The mixture was cooled toroom temperature and purified using silica gel column chromatography(dichloromethane:methanol=70:1→9:1). The purified product wasconcentrated to dryness under reduced pressure, giving a dark brownpowder of 5-propoxy-4H-benzo[f]quinolin-1-one (3.15 g, yield: 61%).

Reference Example 6

Production of 2-iodo-5-propoxy-4H-benzo[f]quinolin-1-one

5-Propoxy-4H-benzo[f]quinolin-1-one (2.66 g, 10.5 mmol) was suspended inDMF (20 ml). Potassium carbonate (1.63 g, 11.8 mmol) and iodine (2.95 g,11.6 mmol) were added to the suspension, followed by stirring at roomtemperature for 3 hours. The reaction mixture was poured into an aqueoussodium thiosulfate solution (9.14 g, 100 ml), followed by stirring for 5minutes. Ethyl acetate was added to the reaction mixture and stirred.Subsequently, insoluble matter was collected by filtration, and thefiltrate was then separated. The thus-obtained organic layer was washedwith an aqueous saturated sodium chloride solution, and thenconcentrated to dryness under reduced pressure. The residue was added tothe collected insoluble matter, followed by purification using silicagel column chromatography (dichloromethane:methanol=50:1→20:1). Thepurified product was concentrated to dryness under reduced pressure,giving a pale brown powder of 2-iodo-5-propoxy-4H-benzo[f]quinolin-1-one(3.48 g, yield: 87%).

Reference Example 7

Production of 1-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanoneoxime

1-(3-Propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone (8.88 g, 38.2mmol) was dissolved in a mixed solvent of chloroform (20 ml) andmethanol (80 ml). Hydroxylamine hydrochloride (4.05 g, 58.2 mmol) andpyridine (9.46 ml, 117 mmol) were added to the solution and stirred for16 hours while heating under reflux. The reaction mixture was cooled toroom temperature, and then concentrated to dryness under reducedpressure. 2N hydrochloric acid (30 ml) and water were added to theresidue, followed by extraction using dichloromethane. The thus-obtainedorganic layer was concentrated to dryness under reduced pressure, andthe residue was then purified using silica gel column chromatography(n-hexane:ethyl acetate=5:1). The purified product was concentrated todryness under reduced pressure, giving a pale yellow powder of1-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone oxime (8.87 g,yield: 94%).

Reference Example 8

Production of N-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide

Indium chloride (1.19 g, 5.39 mmol) was added to an acetonitrilesolution (150 ml) of1-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone oxime (8.87 g,35.8 mmol) and the mixture was stirred for 3 hours while heating underreflux. The reaction mixture was cooled to room temperature, and thenconcentrated to dryness under reduced pressure. Water was added to theresidue, followed by extraction using dichloromethane. The thus-obtainedorganic layer was concentrated to dryness under reduced pressure, andthe residue was then purified using silica gel column chromatography(n-hexane:ethyl acetate=3:1). The purified product was concentrated todryness under reduced pressure, giving a white powder ofN-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (8.65 g, yield:98%).

Reference Example 9

Production of 3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylamine

3-Propoxy-5,6,7,8-tetrahydronaphthalen-2-ylamine was produced in thesame manner as in Reference Example 3.

Reference Example 10

Production of 5-bromo-6-propoxyindan

5-Bromo-6-propoxyindan was produced in the same manner as in ReferenceExample 2.

Reference Example 11

Production of 6-propoxy-indan-5-ylamine

To a 5-bromo-6-propoxyindan (8.24 g, 32.2 mmol) toluene solution (80 ml)were added a benzophenone imine (6.40 g, 35.3 mmol) toluene solution (40ml), tris(dibenzylideneacetone)dipalladium (742 mg, 0.8 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS, 936 mg, 1.6mmol), and cesium carbonate (15.72 g, 48.3 mmol). The resulting mixturewas stirred at 100° C. under a nitrogen atmosphere for 47 hours, andthen cooled to room temperature. Water and saturated ammonium chloridesolution were added to the reaction mixture, followed by extractionusing ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, and then concentrated to dryness under reducedpressure. The generated residue was dissolved in diethyl ether (130 ml).Concentrated hydrochloric acid (25 ml) was added to the solution,followed by stirring for 2 hours. A 5N aqueous sodium hydroxide solution(72 ml) was added to the reaction mixture to adjust its pH to 11,followed by concentration under reduced pressure. The residue wasdissolved in dichloromethane and washed with an aqueous saturated sodiumchloride solution. The thus-obtained organic layer was concentrated todryness under reduced pressure, and the generated residue was thenpurified using silica gel column chromatography (dichloromethane:ethylacetate=90:1). The purified product was concentrated to dryness underreduced pressure, giving a pale brown oily substance of6-propoxy-indan-5-ylamine (1.02 g, yield: 17%).

Reference Example 12

Production of 1-(7-propoxychroman-6-yl)ethanone

1-(7-Hydroxychroman-6-yl)ethanone (3.0 g, 15.6 mmol) was dissolved inDMF (20 ml). Sodium hydride (60% oil base, 686 mg, 1.1 equivalentweight) was added thereto while ice cooling, and then stirred for 10minutes. 1-Iodopropane (2.92 g, 1.1 equivalent weight) was added to themixture and then stirred at room temperature for 3 hours. Water wasadded to the reaction mixture, followed by extraction using ethylacetate. The thus-obtained organic layer was concentrated to drynessunder reduced pressure, and the residue was then purified using silicagel column chromatography (n-hexane:ethyl acetate=1:0→0:1). The purifiedproduct was concentrated to dryness under reduced pressure, giving awhite powder of 1-(7-propoxychroman-6-yl)ethanone (4.2 g, yield:quantitative).

Reference Example 13

Production of 1-(7-propoxychroman-6-yl)ethanone oxime

1-(7-Propoxychroman-6-yl)ethanone oxime was produced in the same manneras in Reference Example 7.

Reference Example 14

Production of N-(7-propoxychroman-6-yl)acetamide

N-(7-propoxychroman-6-yl)acetamide was produced in the same manner as inReference Example 8.

Reference Example 15

Production of 7-propoxychroman-6-ylamine

7-Propoxychroman-6-ylamine was produced in the same manner as inReference Example 3.

Reference Example 16

Production of 1-(6-propoxychroman-7-yl)ethanone oxime

1-(6-Propoxychroman-7-yl)ethanone oxime was produced in the same manneras in Reference Example 7.

Reference Example 17

Production of N-(6-propoxychroman-7-yl)acetamide

N-(6-Propoxychroman-7-yl)acetamide was produced in the same manner as inReference Example 8.

Reference Example 18

Production of 6-propoxychroman-7-ylamine

6-Propoxychroman-7-ylamine was produced in the same manner as inReference Example 3.

Reference Example 19

Production of 1-(5-propoxy-2,3-dihydrobenzofuran-6-yl)ethanone

1-(5-Propoxy-2,3-dihydrobenzofuran-6-yl)ethanone was produced in thesame manner as in Reference Example 12.

Reference Example 20

Production of 1-(5-propoxy-2,3-dihydrobenzofuran-6-yl)ethanone oxime

1-(5-Propoxy-2,3-dihydrobenzofuran-6-yl)ethanone oxime was produced inthe same manner as in Reference Example 7.

Reference Example 21

Production of N-(5-propoxy-2,3-dihydrobenzofuran-6-yl)acetamide

N-(5-Propoxy-2,3-dihydrobenzofuran-6-yl)acetamide was produced in thesame manner as in Reference Example 8.

Reference Example 22

Production of 5-propoxy-2,3-dihydrobenzofuran-6-ylamine

5-Propoxy-2,3-dihydrobenzofuran-6-ylamine was produced in the samemanner as in Reference Example 3.

Reference Example 23

Production of benzhydrylidene(5-methylbenzofuran-7-yl)amine

To a 7-bromo-5-methylbenzofuran (9.71 g, 46 mmol) toluene solution (100ml) were added a benzophenone imine (10.25 g, 56 mmol) toluene solution(55 ml), tris(dibenzylideneacetone)dipalladium (1.1 g, 1 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 2.1 g, 3.45 mmol),and sodium t-butoxide (3.1 g, 31 mmol). The resulting mixture was thenstirred for 4 hours while heating under reflux in a nitrogen atmosphere.The reaction mixture was cooled to room temperature, and water andsaturated ammonium chloride solution were added thereto, followed byextraction using ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate and then concentrated to dryness underreduced pressure. The residue was purified using silica gel columnchromatography (n-hexane:ethyl acetate=10:1). The solvent was removedunder a reduced pressure, giving a yellow oily substance ofbenzhydrylidene(5-methylbenzofuran-7-yl) amine (17.9 g, yield: 81%).

Reference Example 24

Production of 5-methylbenzofuran-7-ylamine

Benzhydrylidene(5-methylbenzofuran-7-yl)amine (17.9 g, 0.57 mmol) wasdissolved in THF (150 ml). 5N Hydrochloric acid (50 ml) was addedthereto, followed by stirring at room temperature for 2 hours. A 5Naqueous sodium hydroxide solution (40 ml) was added to the reactionmixture, followed by extraction using ethyl acetate. The extract wassequentially washed with an aqueous saturated sodium hydrogen solutionand an aqueous saturated sodium chloride solution. The organic layer wasdried over magnesium sulfate and concentrated to dryness under reducedpressure. The residue was purified using silica gel columnchromatography (n-hexane:ethyl acetate=50:1→10:1). The purified productwas concentrated to dryness under reduced pressure, giving a dark brownoily substance of 5-methylbenzofuran-7-ylamine (2.5 g, yield: 30%).

Reference Example 25

Production of 5-methyl-2,3-dihydrobenzofuran-7-ylamine

5-Methylbenzofuran-7-ylamine (1.3 g, 8.8 mmol) and 10% palladium carbon(500 mg) were added to ethanol (50 ml), followed by conduction ofcatalytic reduction at room temperature under ordinary pressure. Thecatalyst was removed by celite filtration, and the obtained filtrate wascondensed under reduced pressure. The residue was dissolved indichloromethane, dried over anhydrous magnesium sulfate, and thenconcentrated to dryness under reduced pressure, giving a white powder of5-methyl-2,3-dihydrobenzofuran-7-ylamine (1.15 g, yield: 87%).

Example 1

Production of 2-(4-methoxyphenyl)-5-propoxy-4H-benzo[f]quinolin-1-one

To a benzene solution (50 ml) containing 3-propoxynaphthalen-2-ylamine(2.05 g, 10.18 mmol) and ethylα-(hydroxymethylene)-4-methoxyphenylacetate (2.29 g, 10.3 mmol) wasadded 350 mg of Amberlyst 15 (Sigma-Aldrich). The resulting mixture washeated under reflux for 21 hours using a Dean-Stark trap. The reactionmixture was then cooled to room temperature, filtered to remove resin,and then the filtrate was concentrated under reduced pressure. Diphenylether (2.2 ml) was added to the residue, and the mixture was then heatedwith a mantle heater and stirred for 1.5 hours under reflux. Theresulting reaction mixture was cooled to room temperature, and thendirectly purified using silica gel column chromatography(dichloromethane:methanol=100:1→60:1). The purified product wasconcentrated under reduced pressure to recrystallize the residue fromethyl acetate-n-hexane, giving a pale yellow powder of2-(4-methoxyphenyl)-5-propoxy-4H-benzo[f]quinolin-1-one (1.55 g, yield:42%).

Melting point: 172-174° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.08 (3H, t, J=7.3 Hz), 1.87-1.95 (2H, m), 3.77(3H, s), 4.22 (2H, t, J=6.5 Hz), 6.97 (2H, d, J=8.8 Hz), 7.47-7.52 (3H,m), 7.64 (2H, d, J=8.8 Hz), 7.83-7.87 (1H, m), 7.92 (1H, s), 10.24-10.28(1H, m), 11.60 (1H, brs).

Example 2

Production of 2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one

3-Iodo-5-propoxy-4H-benzo[f]quinolin-1-one (1.06 g, 2.79 mmol) wassuspended in dimethoxyethane (20 ml). Furan-3-boron acid (354 mg, 3.16mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (PdCl₂(DPPF).CH₂Cl₂, 123 mg, 0.11 mmol) anda 2N aqueous sodium carbonate solution (4.0 ml) were sequentially addedto the suspension. The mixture was stirred at 90 to 100° C. under anitrogen atmosphere for hours. The reaction mixture was cooled to roomtemperature, water was added thereto, and the resulting mixture wassubjected to extraction using dichloromethane. The thus-obtained organiclayer was concentrated under reduced pressure, and the residue waspurified using silica gel column chromatography (dichloromethane:ethylacetate=80:1). The purified product was concentrated under reducedpressure, the residue was washed with ethyl acetate and then dried,giving a pale brown powder of2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one (430 mg, yield: 48%).

Melting point: 252-254° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.10 (3H, t, J=7.4 Hz), 1.87-1.98 (2H, m), 4.27(2H, t, J=6.5 Hz), 7.03 (1H, s), 7.48-7.55 (2H, m), 7.57 (1H, s), 7.72(1H, s), 7.84-7.89 (1H, m), 8.22 (1H, s), 8.71 (1H, s), 10.24-10.30 (1H,m), 11.80 (1H, brs).

Example 3

Production of 2-furan-3-yl-4-methyl-5-propoxy-4H-benzo[f]quinolin-1-one

To a DMF solution (5 ml) of2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one (300 mg, 0.94 mmol) wasadded sodium hydride (60% oil base, 61 mg, 1.4 mmol), and then themixture was stirred at room temperature for 5 minutes. Methyl iodide(181 mg, 1.27 mmol) was added thereto and the resulting mixture wasstirred at room temperature for 62 hours. Water and ethyl acetate wereadded to the reaction mixture and the resulting mixture was subjected toseparation. The thus-obtained organic layer was washed with water, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was purified using silica gel columnchromatography (dichloromethane:ethyl acetate=90:1→80:1). The purifiedproduct was concentrated under reduced pressure to recrystallize theresidue from ethyl acetate-n-hexane, giving a pale gray powder of2-furan-3-yl-4-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (130 mg,yield: 42%).

Melting point: 165-167° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.05 (3H, t, J=7.4 Hz), 1.83-1.92 (2H, m), 4.12(2H, t, J=6.4 Hz), 4.21 (3H, s), 7.07 (1H, s), 7.45-7.51 (2H, m), 7.54(1H, s), 7.70 (1H, s), 7.79-7.83 (1H, m), 8.36 (1H, s), 8.69 (1H, s),10.34-10.38 (1H, m).

Example 4

Production of 5-propoxy-2-thiophen-2-yl-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Pale Brown Powder (Ethanol)

Melting point: 298-300° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.10 (3H, t, J=7.4 Hz), 1.87-2.01 (2H, m), 4.27(2H, t, J=6.5 Hz), 7.12 (1H, dd, J=3.9 Hz, 5.1 Hz), 7.47 (1H, d, J=4.7Hz), 7.52-7.57 (2H, m), 7.59 (1H, s), 7.66 (1H, d, J=3.7 Hz), 7.87-7.91(1H, m), 8.50 (1H, s), 10.20-10.27 (1H, m), 11.95 (1H, brs).

Example 5

Production of4-methyl-5-propoxy-2-thiophen-2-yl-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 3 usingappropriate starting material.

Pale Yellow Powder (Ethyl Acetate)

Melting point: 193-195° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.05 (3H, t, J=7.4 Hz), 1.84-1.92 (2H, m), 4.12(2H, t, J=6.4 Hz), 4.23 (3H, s), 7.09-7.13 (1H, m), 7.46-7.55 (4H, m),7.66 (1H, d, J=3.7 Hz), 7.80-7.84 (1H, m), 8.63 (1H, s), 10.32-10.36(1H, m).

Example 6

Production of 5-propoxy-2-thiophen-3-yl-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Pale Brown Powder

¹H-NMR (DMSO-d₆) δ ppm: 1.10 (3H, t, J=7.3 Hz), 1.90-1.98 (2H, m), 4.27(2H, t, J=6.5 Hz), 7.49-7.58 (4H, m), 7.63-7.66 (1H, m), 7.85-8.00 (1H,m), 8.24 (1H, s), 8.34-8.36 (1H, m), 10.23-10.29 (1H, m), 11.71 (1H,brs).

Example 7

Production of4-methyl-5-propoxy-2-thiophen-3-yl-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 3 usingappropriate starting material.

White Powder

¹H-NMR (DMSO-d₆) δ ppm: 1.05 (3H, t, J=7.4 Hz), 1.84-1.92 (2H, m), 4.12(2H, t, J=6.4 Hz), 4.19 (3H, s), 7.44-7.57 (4H, m), 7.70 (1H, d, J=5.1Hz), 7.80-7.84 (1H, m), 8.38-8.40 (2H, brs), 10.30-10.34 (1H, m).

Example 8

Production of2-(4-methoxyphenyl)-3-methyl-5-propoxy-4H-benzo[f]quinolin-1-one

To a benzene solution (38 ml) containing 3-propoxynaphthalen-2-ylamine(600 mg, 2.98 mmol) and ethyl α-acetyl-4-methoxyphenylacetate (1.41 g,5.96 mmol) was added 85 mg of Amberlyst 15 (Sigma-Aldrich). Theresulting mixture was heated under reflux for 20 hours using aDean-Stark trap. The reaction mixture was cooled to room temperature,filtered to remove resin, and then the filtrate was concentrated underreduced pressure. Diphenyl ether (2.8 ml) was added to the residue, andthe mixture was then heated with a mantle heater and stirred for 70minutes under reflux. The resulting reaction mixture was cooled to roomtemperature, and then directly purified using silica gel columnchromatography (dichloromethane:methanol=80:1→70:1). The purifiedproduct was concentrated under reduced pressure, giving an oilysubstance (800 mg, yield: 72%). Ethyl acetate and n-hexane were added tothe thus-obtained oily substance to crystallize and then recrystallizedfrom ethyl acetate, giving a pale yellow powder of2-(4-methoxyphenyl)-3-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (290mg).

Melting point: 204-206° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.05 (3H, t, J=7.4 Hz), 1.90-1.98 (2H, m), 2.31(3H, s), 3.77 (3H, s), 4.27 (2H, t, J=6.8 Hz), 6.95 (2H, d, J=8.6 Hz),7.17 (2H, d, J=8.6 Hz), 7.39-7.50 (2H, m), 7.56 (1H, s), 7.84 (1H, dd,J=2.2 Hz, 6.5 Hz), 10.09-10.13 (1H, m), 10.79 (1H, brs).

Example 9

Production of3-methyl-5-propoxy-2-thiophen-3-yl-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 8 usingappropriate starting material.

Pale Gray Powder (Ethyl Acetate)

Melting point: 186-188° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (3H, t, J=7.3 Hz), 1.88-1.97 (2H, m), 2.40(3H, s), 4.26 (2H, t, J=6.7 Hz), 7.14 (1H, d, J=4.9 Hz), 7.41-7.54 (5H,m), 7.83 (1H, d, J=6.6 Hz), 10.07-10.11 (1H, m), 10.84 (1H, brs).

Example 10

Production of5-propoxy-8-thiophen-2-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

Yellow Powder

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (3H, t, J=7.4 Hz), 1.77-1.88 (2H, m),1.97-2.08 (2H, m), 2.86 (2H, t, J=7.5 Hz), 3.45 (2H, t, J=7.0 Hz), 4.10(2H, t, J=6.5 Hz), 7.05 (1H, t, J=3.8 Hz), 7.13 (1H, s), 7.36 (1H, d,J=5.1 Hz), 7.53 (1H, d, J=3.6 Hz), 8.31 (1H, s), 11.39 (1H, brs).

Example 11

Production of6-methyl-5-propoxy-8-thiophen-2-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 3 usingappropriate starting materials.

Orange Color Powder

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.4 Hz), 1.77-1.85 (2H, m),1.97-2.03 (2H, m), 2.84 (2H, t, J=7.6 Hz), 3.49 (2H, t, J=7.1 Hz), 4.00(2H, t, J=6.4 Hz), 4.13 (3H, s), 7.05 (1H, t, J=3.8 Hz), 7.18 (1H, s),7.35 (1H, d, J=4.7 Hz), 7.54 (1H, d, J=3.3 Hz), 8.48 (1H, s).

Example 12

Production of5-propoxy-8-thiophen-3-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

Pale Brown Powder

¹H-NMR (DMSO-d₆) δ ppm: 1.03 (3H, t, J=7.4 Hz), 1.76-1.87 (2H, m),1.95-2.07 (2H, m), 2.85 (2H, t, J=7.5 Hz), 3.30-3.55 (2H, m), 4.09 (2H,t, J=6.5 Hz), 7.11 (1H, s), 7.48-7.56 (2H, m), 8.11 (1H, d, J=6.2 Hz),8.21-8.23 (1H, m), 11.18 (1H, d, J=5.8 Hz).

Example 13

Production of6-methyl-5-propoxy-8-thiophen-3-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 3 usingappropriate starting materials.

Pale Yellow Powder

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.4 Hz), 1.76-1.85 (2H, m),1.95-2.01 (2H, m), 2.83 (2H, t, J=7.6 Hz), 3.49 (2H, t, J=7.4 Hz), 3.99(2H, t, J=6.5 Hz), 4.09 (3H, s), 7.15 (1H, s), 7.48-7.52 (1H, m),7.63-7.65 (1H, m), 8.26-8.28 (2H, m).

Example 14

Production of8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

Pale Brown Powder (Ethyl Acetate)

Melting point: 206-208° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.4 Hz), 1.78-1.86 (2H, m),1.96-2.02 (2H, m), 2.83 (2H, t, J=7.5 Hz), 3.40 (2H, t, J=7.3 Hz), 3.74(3H, s), 4.07 (2H, t, J=6.4 Hz), 6.91 (2H, d, J=8.8 Hz), 7.09 (1H, s),7.55 (2H, d, J=8.8 Hz), 7.78 (1H, d, J=5.9 Hz), 11.06 (1H, d, J=5.8 Hz).

Example 15

Production of8-(4-methoxyphenyl)-7-methyl-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 8 usingappropriate starting material.

Pale Yellow Powder (Ethyl Acetate)

Melting point: 223-225° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.4 Hz), 1.79-1.87 (2H, m),1.93-1.99 (2H, m), 2.21 (3H, s), 2.82 (2H, t, J=7.4 Hz), 3.31 (2H, t,J=7.1 Hz), 3.75 (3H, s), 4.10 (2H, t, J=6.7 Hz), 6.90 (2H, d, J=8.7 Hz),7.08 (2H, d, J=8.5 Hz), 7.10 (1H, s), 10.30 (1H, brs).

Example 16

Production of7-methyl-5-propoxy-8-thiophen-3-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 8 usingappropriate starting materials.

Pale Brown Powder (Ethyl Acetate)

Melting point: 260-262° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.3 Hz), 1.79-1.87 (2H, m),1.90-1.99 (2H, m), 2.31 (3H, s), 2.82 (2H, t, J=7.5 Hz), 3.32 (2H, t,J=7.3 Hz), 4.09 (2H, t, J=6.7 Hz), 7.04-7.10 (2H, m), 7.31-7.32 (1H, m),7.44-7.47 (1H, m), 10.35 (1H, brs).

Example 17

Production of6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

To a DMF solution (6 ml) of8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one(1.26 g, 3.60 mmol) was added sodium hydride (60% oil base, 189 mg, 4.33mmol). The mixture was stirred at room temperature for 10 minutes. Tothe resulting mixture was added 1-bromo-3-chloropropane (1.70 g, 10.8mmol), followed by stirring at room temperature for 16 hours. Water andethyl acetate were added to the reaction mixture and the resultingreaction mixture was then subjected to separation. The thus-obtainedorganic layer was washed with an aqueous saturated sodium chloridesolution twice. After being dried over anhydrous sodium sulfate, theorganic layer was concentrated under reduced pressure. The residue waspurified using silica gel column chromatography (dichloromethane:ethylacetate=20:1→12:1). The purified product was concentrated under reducedpressure, giving a yellow oily substance of6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one(365 mg, yield: 92%).

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, m), 1.90-2.24 (6H, m), 2.91 (2H, t,J=7.6 Hz), 3.45 (2H, t, J=5.7 Hz), 3.67 (2H, t, J=7.5 Hz), 3.83 (3H, s),4.04 (2H, t, J=6.7 Hz), 4.71 (2H, t, J=6.4 Hz), 6.92-7.04 (3H, m),7.58-7.62 (3H, m).

Example 18

Production of8-(4-methoxyphenyl)-6-(3-morpholin-4-ylpropyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

A mixture containing6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one(700 mg, 1.64 mmol), morpholine (165 mg, 1.90 mmol), potassium carbonate(341 mg, 2.47 mmol), sodium iodide (295 mg, 1.97 mmol) and dimethylformamide (3 ml) was stirred at 60° C. for 7 hours. Water and ethylacetate were added to the reaction mixture, followed by separation. Thethus-obtained organic layer was washed with an aqueous saturated sodiumchloride solution twice and then concentrated under reduced pressure.The residue was purified using silica gel column chromatography(dichloromethane:methanol=70:1→50:1). The purified product wasconcentrated under reduced pressure to recrystallize the residue fromethyl acetate-n-hexane, giving a white powder of8-(4-methoxyphenyl)-6-(3-morpholin-4-ylpropyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one(295 mg, yield: 38%).

Melting point: 135-137° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.75-1.85 (4H, m), 1.96(2H, t, J=7.5 Hz), 2.04-2.15 (6H, m), 2.83 (2H, t, J=7.5 Hz), 3.38-3.41(6H, m), 3.74 (3H, s), 4.02 (2H, t, J=6.5 Hz), 4.55 (2H, t, J=6.2 Hz),6.90 (2H, d, J=8.7 Hz), 7.18 (1H, s), 7.60 (2H, d, J=8.7 Hz), 7.93 (1H,s).

Example 19

Production of8-(4-methoxyphenyl)-6-(3-piperidin-1-ylpropyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 18using appropriate starting material.

Pale Yellow Powder (Ethyl Acetate-n-hexane)

Melting point: 99-101° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.20-1.50 (6H, m),1.74-1.86 (4H, m), 1.96 (2H, t, J=7.4 Hz), 2.02-2.20 (6H, m), 2.83 (2H,t, J=7.3 Hz), 3.30-3.40 (2H, m), 3.74 (3H, s), 4.02 (2H, t, J=6.4 Hz),4.53 (2H, t, J=5.8 Hz), 6.90 (2H, d, J=8.7 Hz), 7.18 (1H, s), 7.60 (2H,d, J=8.7 Hz), 7.91 (1H, s).

Example 20

Production of6-(3-chloropropyl)-5-propoxy-8-thiophen-3-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 17using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, m), 1.88-2.25 (6H, m), 2.91 (2H, t,J=7.6 Hz), 3.45 (2H, t, J=5.8 Hz), 3.69 (2H, t, J=7.5 Hz), 4.01-4.04(2H, m), 4.74 (2H, t, J=6.4 Hz), 7.05 (1H, s), 7.32-7.35 (1H, m),7.43-7.47 (1H, m), 7.83 (1H, s), 8.08-8.10 (1H, m).

Example 21

Production of6-(3-morpholin-4-ylpropyl)-5-propoxy-8-thiophen-3-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Pale Yellow Powder (Ethyl Acetate)

Melting point: 163-165° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.76-1.86 (4H, m), 1.98(2H, t, J=7.5 Hz), 2.03-2.20 (6H, m), 2.84 (2H, t, J=7.5 Hz), 3.41-3.52(6H, m), 4.02 (2H, t, J=6.5 Hz), 4.60 (2H, t, J=6.3 Hz), 7.18 (1H, s),7.49-7.52 (1H, m), 7.62-7.64 (1H, m), 8.25-8.27 (1H, m), 8.30 (1H, s).

Example 22

Production of6-(3-[1,4]oxazepan-4-ylpropyl)-5-propoxy-8-thiophen-3-yl-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Pale Brown Powder (Ethyl Acetate)

Melting point: 146-148° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.60-1.64 (2H, m),1.74-1.86 (4H, m), 1.98 (2H, t, J=7.4 Hz), 2.19 (2H, t, J=6.3 Hz),2.40-2.45 (4H, m), 2.84 (2H, t, J=7.4 Hz), 3.51-3.59 (6H, m), 4.03 (2H,t, J=6.4 Hz), 4.60 (2H, t, J=6.0 Hz), 7.19 (1H, s), 7.48-7.51 (1H, m),7.61 (1H, d, J=4.9 Hz), 8.23 (1H, d, J=1.8 Hz), 8.27 (1H, s).

Example 23

Production of di-tert-butyl8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethylphosphate

To a DMF solution (10 ml) of8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one(400 mg, 1.15 mmol) and sodium iodide (343 mg, 2.29 mmol) was addedsodium hydride (60% oil base, 74.9 mg, 1.72 mmol), and the mixture wasthen stirred for 10 minutes at room temperature. To the resultingmixture was added a DMF solution (20 ml) of di-tert-butyl chloromethylphosphate (888 mg, 3.43 mmol), and the mixture was then stirred at 40°C. for 4 hours. The reaction mixture was ice-cooled, ice water was addedthereto, and then the reaction mixture was subjected to extraction usingethyl acetate. The thus-obtained organic layer was washed with anaqueous saturated sodium chloride solution twice, dried over anhydroussodium sulfate and then concentrated under reduced pressure. The residuewas purified using medium pressure liquid chromatography (NH silica gel,n-hexane:ethyl acetate=100:0→0:100). The purified product wasconcentrated under reduced pressure, giving a white powder ofdi-tert-butyl8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethylphosphate (263 mg, yield: 40%).

¹H-NMR (CDCl₃) δ ppm: 1.08-1.14 (3H, t, J=7.4 Hz), 1.35 (18H, s),1.88-2.16 (4H, m), 2.88-2.95 (2H, t, J=7.7 Hz), 3.60-3.66 (2H, t, J=7.5Hz), 3.82 (3H, s), 4.05-4.10 (2H, t, J=6.7 Hz), 6.30-6.35 (2H, d, J=12.4Hz), 6.90-6.97 (2H, d, J=8.8 Hz), 7.09 (1H, s), 7.57-7.63 (2H, d, J=8.8Hz), 7.76 (1H, s).

Example 24

Production of[8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethyl]monophosphate

A dichloromethane solution (4 ml) of di-tert-butyl8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethylester (263 mg, 0.46 mmol) was ice-cooled, trifluoroacetic acid (1.2 ml)and dichloromethane (4 ml) were added thereto under a nitrogenatmosphere and the resulting mixture was stirred at 0° C. for 1 hour.This mixture was concentrated under reduced pressure. The residue wassubjected to vacuum drying, giving a pale yellow powder of[8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethyl]monophosphate(147 mg, yield: 56%).

¹H-NMR (DMSO-d₆) δ ppm: 1.01-1.04 (3H, t, J=7.4 Hz), 1.78-1.86 (2H, m),1.96-2.02 (2H, m), 2.83 (2H, t, J=7.5 Hz), 3.40 (2H, t, J=7.3 Hz), 3.74(3H, s), 4.07 (2H, t, J=6.4 Hz), 6.25-6.30 (2H, d, J=10.42 Hz),6.92-6.95 (2H, m), 7.13 (1H, s), 7.59-7.63 (2H, d, J=8.8 Hz), 7.76-7.79(1H, d, J=5.9 Hz).

Example 25

Production of[8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethyl]monophosphatedisodium salt

[8-(4-Methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethyl]monophosphate(147 mg, 0.32 mmol) was suspended in isopropyl alcohol (20 ml), and 1Naqueous sodium hydroxide solution (0.64 ml, 0.64 mmol) was then addedthereto under a nitrogen atmosphere at 0° C. The resulting mixture wasstirred for 1 hour at 0° C. The generated insoluble matter was separatedand washed with acetone and dried, giving a white powder of[8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethyl]monophosphatedisodium salt (42 mg, yield: 26%)

¹H-NMR (D₂O) δ ppm: 0.91-0.98 (3H, t, J=7.8 Hz), 1.74-1.83 (2H, m),1.92-1.98 (2H, m), 2.75-2.81 (2H, t, J=7.6 Hz), 3.30-3.36 (2H, t, J=7.2Hz), 3.75 (3H, s), 3.90-3.95 (2H, t, J=6.7 Hz), 5.94-5.99 (2H, d, J=9.5Hz), 6.89-6.93 (2H, d, J=8.8 Hz), 7.15 (1H, s), 7.87-7.94 (2H, d, J=8.8Hz), 8.58 (1H, s).

Example 26

Production of2-(4-methoxyphenyl)-5-propoxy-7,8,9,10-tetrahydro-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Pale Yellow Powder (Ethyl Acetate)

Melting point: 186-187° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.4 Hz), 1.60-1.70 (4H, m),1.78-1.86 (2H, m), 2.70-2.80 (2H, m), 3.30-3.40 (2H, m), 3.74 (3H, s),4.05 (2H, t, J=6.4 Hz), 6.85 (1H, s), 6.90 (2H, d, J=8.7 Hz), 7.50 (2H,d, J=8.7 Hz), 7.72 (1H, d, J=5.1 Hz), 10.95 (1H, d, J=4.7 Hz).

Example 27

Production of5-propoxy-2-thiophen-3-yl-7,8,9,10-tetrahydro-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Pale Brown Powder (Ethyl Acetate)

Melting point: 213-215° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.4 Hz), 1.60-1.70 (4H, m),1.75-1.86 (2H, m), 2.70-2.80 (2H, m), 3.30-3.40 (2H, m), 4.05 (2H, t,J=6.4 Hz), 6.85 (1H, s), 7.46-7.52 (2H, m), 8.06 (1H, s), 8.14-8.15 (1H,m), 11.10 (1H, brs).

Example 28

Production of2-(4-methoxyphenyl)-3-methyl-5-propoxy-7,8,9,10-tetrahydro-4H-benzo[f]quinolin-1-one

The above compound was prepared in the same manner as in Example 8 usingappropriate starting material.

Pale Yellow Powder (Ethyl Acetate)

Melting point: 199-201° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.98 (3H, t, J=7.3 Hz), 1.60-1.70 (4H, m),1.78-1.87 (2H, m), 2.17 (3H, s), 2.70-2.80 (2H, m), 3.20-3.30 (2H, m),3.74 (3H, s), 4.07 (2H, t, J=6.7 Hz), 6.84 (1H, s), 6.88 (2H, d, J=8.7Hz), 7.06 (2H, d, J=8.5 Hz), 10.17 (1H, brs).

Example 29

Production of3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-oxa-1-aza-phenanthren-4-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Melting point: 222-223° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.06 (3H, t, J=7.5 Hz), 1.74-1.95 (4H, m),2.72-2.75 (2H, t, J=6.5 Hz), 3.75 (3H, s), 4.00-4.10 (4H, m), 6.87-6.93(3H, m), 7.46-7.52 (2H, d, J=9.0 Hz), 7.65 (1H, s), 10.70-10.90 (1H,brs).

Example 30

Production of1-{3-[4-(2-methoxyethyl)piperazin-1-yl]propyl}-3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-oxa-1-aza-phenanthren-4-onedihydrochloride

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Melting point: 145-147° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01-1.06 (3H, t, J=7.4 Hz), 1.85-2.02 (4H, m),2.12-2.33 (2H, m), 2.84-2.89 (2H, t, J=6.3 Hz), 3.02-3.20 (2H, m),3.28-3.80 (15H, m), 4.08-4.13 (2H, t, J=6.8 Hz), 4.28-4.31 (2H, t, J=4.6Hz), 4.75-4.95 (2H, m), 7.00-7.03 (2H, d, J=8.9 Hz), 7.30 (1H, s),7.63-7.66 (2H, d, J=8.9 Hz), 8.48 (1H, s).

Example 31

Production ofethyl[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetate

Sodium hydride (60% oil base, 80 mg, 2.0 mmol) was added to a DMFsolution (10 ml) of3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-oxa-1-aza-phenanthren-4-one(600 mg, 1.64 mmol), the resulting mixture was then stirred at roomtemperature for 5 minutes. Ethyl bromoacetate (330 mg, 2.0 mmol) wasadded thereto and the resulting mixture was stirred at room temperaturefor 16 hours. Water and ethyl acetate were added to the reactionmixture, followed by separation. The thus-obtained organic layer waswashed with water, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The residue was purified usingmedium pressure liquid chromatography (NH silica gel, n-hexane:ethylacetate=100:0→0:100). The purified product was concentrated underreduced pressure, giving a colorless oily substanceethyl[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetate(700 mg, yield: 95%).

¹H-NMR (CDCl₃) δ ppm: 1.00-1.10 (3H, t, J=7.5 Hz), 1.25-1.28 (3H, t,J=6.0), 1.75-1.90 (2H, m), 2.02-2.43 (2H, m), 2.80-2.90 (2H, m), 3.85(3H, s), 3.86-3.88 (2H, m), 4.10-4.13 (4H, m), 5.10 (2H, s), 6.75 (1H,s), 6.85-6.90 (2H, d, J=9.0), 7.24 (1H, s), 7.60-7.75 (2H, d, J=9.0).

Example 32

Production of[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]aceticacid

A 5N aqueous sodium hydroxide solution (10 ml) was added to an ethanolsolution (30 ml) ofethyl[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetate(700 mg, 1.55 mmol) and heated for 2 hours under reflux. The mixture wascooled to room temperature and concentrated under reduced pressure.While ice-cooling the concentrate, water and concentrated hydrochloricacid were added to the residue to make it acidic. Subsequently, theformed insoluble matter was separated and dried, giving a yellow powderof[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]aceticacid (580 mg, yield: 88%).

¹H-NMR (DMSO-d₆) δ ppm: 0.94-1.00 (3H, t, J=7.5 Hz), 1.74-1.82 (2H, m),1.94-1.98 (2H, m), 2.78-2.83 (2H, t, J=6.2 Hz), 3.77 (3H, s), 3.92-3.98(2H, t, J=6.7 Hz), 4.21-4.25 (2H, t, J=4.8 Hz), 5.35 (2H, s), 6.96-7.00(2H, d, J=8.8 Hz), 7.16 (1H, s), 7.56-7.59 (2H, d, J=8.8 Hz), 8.29 (1H,s).

Example 33

Production of2-[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]-N-(2-morpholin-4-ylethyl)acetamide

4-(2-Aminoethyl)morpholine (217 mg, 1.7 mmol) was added to a DMFsolution (10 ml) of[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]aceticacid (580 mg, 1.39 mmol),2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HATU, 790 mg, 2.1 mmol) and triethylamine (5 ml).The mixture was stirred overnight at room temperature and thenconcentrated under reduced pressure. Water and ethyl acetate were addedto the residue, followed by separation. The thus-obtained organic layerwas washed with water and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography(dichloromethane:methanol=10:1). The purified product was concentratedunder reduced pressure, and the residue was recrystallized from ethylacetate, giving a pale brown powder of2-[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]-N-(2-morpholin-4-ylethyl)acetamide(115 mg, yield: 16%).

Melting point: 201-203° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.94-1.00 (3H, t, J=7.5 Hz), 1.71-1.77 (2H, m),1.91-1.93 (2H, m), 2.29-2.34 (4H, m), 2.72-2.75 (2H, t, J=6.2 Hz),3.15-3.19 (2H, m), 3.25-3.30 (2H, m), 3.33-3.54 (4H, m), 3.76 (3H, s),3.85-3.90 (2H, t, J=6.7 Hz), 4.07-4.11 (2H, m), 5.06 (2H, s), 6.90-6.93(3H, m), 7.54-7.58 (2H, m), 7.72 (1H, s), 7.80-7.82 (1H, m).

Example 34

Production of di-tert-butyl3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.06-1.12 (3H, t, J=7.4 Hz), 1.36 (18H, s),1.88-1.96 (2H, m), 2.01-2.10 (2H, m), 3.82 (3H, s), 3.98-4.03 (2H, t,J=6.7 Hz), 4.28-4.32 (2H, t, J=5.1 Hz), 6.25-6.31 (2H, d, J=12.2 Hz),6.85-6.93 (3H, m), 7.60-7.66 (3H, m).

Example 35

Production of[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.99-1.04 (3H, t, J=7.4 Hz), 1.74-1.95 (4H, m),2.72-2.75 (2H, t, J=6.5 Hz), 3.75 (3H, s), 4.00-4.10 (4H, m), 6.20-6.24(2H, d, J=10.3 Hz), 6.92-7.10 (3H, m), 7.53-7.57 (2H, m), 7.86 (1H, s).

Example 36

Production of[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

¹H-NMR (D₂O) δ ppm: 0.91-0.97 (3H, t, J=7.4 Hz), 1.72-1.86 (2H, m),1.90-1.94 (2H, m), 2.70-2.75 (2H, t, J=6.4 Hz), 3.74 (3H, s), 3.91-3.97(3H, t, J=6.8 Hz), 4.11-4.15 (3H, t, J=4.8 Hz), 5.94-5.98 (2H, d, J=8.8Hz), 6.89-6.93 (2H, d, J=8.8 Hz), 7.03 (1H, s), 7.37-7.41 (2H, d, J=8.8Hz), 7.97 (1H, s).

Example 37

Production of9-(4-methoxyphenyl)-6-propoxy-2,3-dihydro-1H,7H-pyrano[3,2-f]quinolin-10-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Melting point: 171-173° C.

¹H-NMR (CDCl₃) δ ppm: 1.03-1.10 (3H, t, J=7.5 Hz), 1.84-2.02 (4H, m),3.52-3.58 (2H, t, J=6.5 Hz), 3.81 (3H, s), 4.02-4.07 (2H, t, J=6.6 Hz),4.16-4.19 (2H, t, J=5.1 Hz), 6.58 (1H, s), 6.91-6.95 (2H, d, J=9.0 Hz),7.51-7.55 (2H, d, J=9.0 Hz), 7.61-7.64 (1H, d, J=6.2 Hz), 8.86-8.88 (1H,d, J=5.45 Hz).

Example 38

Production ofethyl[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrano[3,2-f]quinolin-7-yl]acetate

The above compound was prepared in the same manner as in Example 31using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.01-1.07 (3H, t, J=7.5 Hz), 1.23-1.29 (3H, t,J=7.5 Hz), 1.79-1.85 (2H, m), 1.95-1.98 (2H, m), 3.49-3.54 (2H, t, J=6.5Hz), 3.83 (3H, s), 3.91-3.96 (2H, t, 6.8 Hz), 4.11-4.27 (6H, m), 5.05(2H, s), 6.62 (1H, s), 6.92-6.95 (2H, d, J=8.8 Hz), 7.29 (1H, s),7.54-7.57 (2H, d, J-8.8 Hz).

Example 39

Production of[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrano[3,2-f]quinolin-7-yl]aceticacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.94-1.00 (3H, t, J=7.5 Hz), 1.72-1.86 (4H, m),3.11-3.33 (2H, m), 3.76 (3H, s), 3.90-3.95 (2H, t, J=6.5 Hz), 4.08-4.11(2H, m), 5.17 (2H, s), 6.70 (1H, s), 6.90-6.95 (2H, d, J=8.8 Hz),7.53-7.60 (2H, d, J=8.8 Hz), 8.54 (1H, s), 12.6-12.9 (1H, brs).

Example 40

Production of2-[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrano[3,2-f]quinolin-7-yl]-N-(2-morpholin-4-ylethyl)acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting material.

Melting point: 206-208° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.93-0.98 (3H, t, J=7.3 Hz), 1.66-1.90 (4H, m),3.00-3.20 (4H, m), 3.50-3.62 (2H, m), 3.76 (3H, s), 3.90-3.96 (4H, m),4.04-4.12 (2H, m), 5.07 (2H, s), 6.70 (1H, s), 6.91-6.95 (2H, d, J=8.8Hz), 7.56-7.59 (2H, d, J=8.8 Hz), 7.77 (1H, s), 8.10-8.25 (1H, m).

Example 41

Production of2-[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrano[3,2-f]quinolin-7-yl]-N-(3-morpholin-4-ylpropyl)acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Melting point: 185-187° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.94-1.00 (3H, t, J=7.4 Hz), 1.66-1.96 (6H, m),2.90-3.21 (6H, m), 3.25-3.43 (4H, m), 3.56-3.66 (2H, t, J=11.9 Hz), 3.77(3H, s), 3.85-4.04 (4H, m), 4.05-4.18 (2H, m), 5.09 (2H, s), 6.71 (1H,s), 6.92-6.96 (2H, d, J=8.8 Hz), 7.57-7.61 (2H, d, J=8.8 Hz), 7.79 (1H,s), 8.09-8.14 (1H, t, J=5.5 Hz).

Example 42

Production of7-{3-[4-(2-methoxyethyl)piperazin-1-yl]propyl}-9-(4-methoxyphenyl)-6-propoxy-2,3-dihydro-1H,7H-pyrano[3,2-f]quinolin-10-onedihydrochloride

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Melting point: 180-182° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.05 (3H, t, J=7.4 Hz), 1.83-1.91 (4H, m),2.00-2.20 (2H, m), 3.00-4.50 (20H, m), 4.50-4.70 (2H, m), 6.77 (1H, s),6.90-6.95 (2H, d, J=8.8 Hz), 7.60-7.65 (2H, d, J=8.8 Hz), 7.94 (1H, s).

Example 43

Production of di-tert-butyl9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrano[3,2-f]quinolin-7-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, t, J=7.4 Hz), 1.35 (18H, s),1.89-1.98 (4H, m), 3.46-3.51 (2H, t, J=6.5 Hz), 3.82 (3H, s), 4.01-4.06(2H, t, J=6.6 Hz), 4.16-4.21 (2H, t, J=5.0 Hz), 6.25-6.30 (2H, d, J=12.3Hz), 6.70 (1H, s), 6.91-6.95 (2H, d, J=8.8 Hz), 7.55-7.59 (2H, d, J=8.8Hz), 7.68 (1H, s).

Example 44

Production of[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrano[3,2-f]quinolin-7-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.03-1.10 (3H, t, J=7.5 Hz), 1.84-2.02 (4H, m),3.52-3.58 (2H, t, J=6.5 Hz), 3.81 (3H, s), 4.02-4.07 (2H, t, J=6.6 Hz),4.16-4.19 (2H, t, J=5.1 Hz), 6.15-6.19 (2H, d, J=10.8 Hz), 6.80 (1H, s),6.94-6.96 (2H, d, J=9.0 Hz), 7.52-7.56 (2H, d, J=9.0 Hz), 7.69-7.72 (1H,d, J=6.2 Hz).

Example 45

Production of[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrano[3,2-f]quinolin-7-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

¹H-NMR (D₂O) δ ppm: 0.94-0.99 (2H, t, J=7.4 Hz), 1.81-1.88 (2H, m),3.21-3.23 (2H, m), 3.78 (3H, s), 3.99-4.05 (2H, m), 4.13-4.15 (2H, m),6.04-6.14 (2H, d, J=8.8 Hz), 6.78 (1H, s), 6.96-6.99 (2H, d, J=8.8 Hz),7.39-7.45 (2H, m), 8.08 (1H, s).

Example 46

Production of8-(4-methoxyphenyl)-5-propoxy-3,6-dihydro-2H-flo[2,3-f]quinolin-9-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Pale Brown Powder (Ethyl Acetate)

Melting point: 218-220° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.4 Hz), 1.75-1.83 (2H, m), 3.13(2H, t, J=8.8 Hz), 3.74 (3H, s), 4.02 (2H, t, J=6.5 Hz), 4.54 (2H, t,J=8.9 Hz), 6.91 (2H, d, J=8.7 Hz), 7.15 (1H, s), 7.51 (2H, d, J=8.7 Hz),7.75 (1H, d, J=5.9 Hz), 10.99 (1H, d, J=5.9 Hz).

Example 47

Production of5-propoxy-8-thiophen-3-yl-3,6-dihydro-2H-flo[2,3-f]quinolin-9-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

Pale Brown Powder (Ethanol)

Melting point: 275-277° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.4 Hz), 1.72-1.84 (2H, m), 3.14(2H, t, J=8.9 Hz), 4.02 (2H, t, J=6.5 Hz), 4.55 (2H, t, J=8.9 Hz), 7.15(1H, s), 7.47-7.54 (2H, m), 8.08 (1H, d, J=6.3 Hz), 8.16-8.17 (1H, m),11.10 (1H, d, J=6.1 Hz).

Example 48

Production of8-(4-methoxyphenyl)-7-methyl-5-propoxy-3,6-dihydro-2H-flo[2,3-f]quinolin-9-one

The above compound was prepared in the same manner as in Example 8 usingappropriate starting material.

Pale Brown Powder (Ethyl Acetate-n-hexane)

Melting point: 216-218° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.97 (3H, t, J=7.4 Hz), 1.76-1.84 (2H, m), 2.18(3H, s), 3.11 (2H, t, J=8.9 Hz), 3.74 (3H, s), 4.04 (2H, t, J=6.8 Hz),4.50 (2H, t, J=8.9 Hz), 6.90 (2H, d, J=8.7 Hz), 7.06 (2H, d, J=8.6 Hz),7.15 (1H, s), 10.19 (1H, brs).

Example 49

Production ofethyl[8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-flo[2,3-f]quinolin-6-yl]acetate

The above compound was prepared in the same manner as in Example 31using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.04 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.2 Hz),1.78-1.86 (2H, m), 3.19 (2H, t, J=8.8 Hz), 3.82 (3H, s), 3.91 (2H, t,J=6.9 Hz), 4.22 (2H, q, J=7.2 Hz), 4.75 (2H, t, J=8.9 Hz), 5.05 (2H, s),6.90 (2H, d, J=8.8 Hz), 7.01 (1H, s), 7.31 (1H, s), 7.63 (2H, d, J=8.8Hz).

Example 50

Production of[8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-flo[2,3-f]quinolin-6-yl]aceticacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.04 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.2 Hz),1.78-1.86 (2H, m), 3.19 (2H, t, J=8.8 Hz), 3.82 (3H, s), 3.91 (2H, t,J=6.9 Hz), 4.22 (2H, q, J=7.2 Hz), 4.75 (2H, t, J=8.9 Hz), 5.05 (2H, s),6.90 (2H, d, J=8.8 Hz), 7.01 (1H, s), 7.31 (1H, s), 7.63 (2H, d, J=8.8Hz).

Example 51

Production of2-[8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-flo[2,3-f]quinolin-6-yl]-N-(2-morpholin-4-ylethyl)acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.92 (3H, t, J=7.3 Hz), 1.67-1.76 (2H, m),2.28-2.33 (6H, m), 3.08-3.17 (4H, m), 3.47-3.51 (4H, m), 3.75 (3H, s),3.86 (2H, t, J=6.7 Hz), 4.53 (2H, t, J=8.9 Hz), 5.06 (2H, s), 6.90 (2H,d, J=8.8 Hz), 7.19 (1H, s), 7.54 (2H, d, J=8.8 Hz), 7.74 (1H, s), 7.83(1H, t, J=5.4 Hz).

Example 52

Production of8-(4-methoxyphenyl)-6-(2-morpholin-4-ylethyl)-5-propoxy-3,6-dihydro-2H-flo[2,3-f]quinolin-9-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.3 Hz), 1.74-1.82 (2H, m),2.30-2.33 (4H, m), 2.54 (2H, t, J=5.5 Hz), 3.14 (2H, t, J=8.8 Hz),3.42-3.45 (4H, m), 3.74 (3H, s), 3.97 (2H, t, J=6.5 Hz), 4.50-4.61 (4H,m), 6.92 (2H, d, J=8.8 Hz), 7.25 (1H, s), 7.56 (2H, d, J=8.8 Hz), 7.81(1H, s).

Example 53

Production of di-tert-butyl8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-flo[2,3-f]quinolin-6-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.06-1.12 (3H, t, J=7.4 Hz), 1.36 (18H, s),1.85-1.97 (2H, m), 3.19-3.26 (2H, t, J=9.0 Hz), 3.82 (3H, s), 4.00-4.05(2H, t, J=6.7 Hz), 4.73-4.80 (2H, t, J=9.0 Hz), 6.28-6.34 (2H, d, J=12.6Hz), 6.88-6.94 (2H, d, J=8.8 Hz), 7.11 (1H, s), 7.63-7.70 (2H, d, J=8.8Hz), 7.74 (1H, s).

Example 54

Production of[8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-flo[2,3-f]quinolin-6-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.05 (3H, t, J=7.4 Hz), 1.79-1.90 (2H, m),3.15-3.22 (2H, m), 4.00-4.06 (2H, t, J=6.7 Hz), 4.53-4.62 (2H, m),6.21-6.25 (2H, d, J=10.6 Hz), 6.92-6.97 (2H, m), 7.36 (1H, s), 7.56-7.59(2H, m), 7.90 (1H, s).

Example 55

Production of[8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-flo[2,3-f]quinolin-6-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

¹H-NMR (D₂O) δ ppm: 0.92-0.97 (3H, t, J=7.4 Hz), 1.76-1.84 (2H, m),3.12-3.19 (2H, t, J=8.9 Hz), 3.75 (3H, s), 3.93-3.99 (2H, t, J=6.8 Hz),4.56-4.59 (2H, m), 5.95-5.99 (2H, d, J=8.9 Hz), 6.90-6.94 (2H, d, J=8.8Hz), 7.27 (1H, s), 7.39-7.43 (2H, d, J=8.8 Hz), 8.01 (1H, s).

Example 56

Production of 7-(4-methoxyphenyl)-5-methyl-9H-flo[3,2-h]quinolin-6-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

White Powder (Ethyl Acetate)

¹H-NMR (DMSO-d₆) δ ppm: 2.84 (3H, s), 3.76 (3H, s), 6.89-7.02 (3H, m),7.22 (1H, s), 7.52-7.58 (2H, d, J=8.8 Hz), 7.77 (1H, s), 8.21 (1H, s),12.06 (1H, brs).

Example 57

Production of7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-9H-flo[3,2-h]quinolin-6-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

White Powder

¹H-NMR (DMSO-d₆) δ ppm: 2.73 (3H, s), 3.26-3.33 (2H, t, J=8.8 Hz), 3.75(3H, s), 4.69-4.76 (2H, t, J=8.8 Hz), 6.87-6.93 (3H, m), 7.50-7.53 (2H,d, J=8.9 Hz), 7.64 (1H, s), 11.30 (1H, brs).

Example 58

Production of di-tert-butyl7-(4-methoxyphenyl)-5-methyl-6-oxo-3,6-dihydro-2H-flo[3,2-h]quinolin-9-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.39 (18H, s), 2.86 (3H, s), 3.26-3.33 (2H, t,J=8.8 Hz), 3.83 (3H, s), 4.66-4.73 (2H, t, J=8.9 Hz), 6.21-6.26 (2H, d,J=11.3 Hz), 6.92-6.99 (3H, m), 7.52-7.56 (2H, d, J=8.9 Hz), 7.66 (1H,s).

Example 59

Production of[7-(4-methoxyphenyl)-5-methyl-6-oxo-3,6-dihydro-2H-flo[3,2-h]quinolin-9-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 2.75 (3H, s), 3.26-3.33 (2H, t, J=8.8 Hz), 3.75(3H, s), 4.69-4.76 (2H, t, J=8.8 Hz), 6.15-6.19 (2H, d, J=10.8 Hz),6.90-6.97 (3H, m), 7.52-7.58 (2H, d, J=8.9 Hz), 7.64 (1H, s).

Example 60

Production of[7-(4-methoxyphenyl)-5-methyl-6-oxo-3,6-dihydro-2H-flo[3,2-h]quinolin-9-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

¹H-NMR (D₂O) δ ppm: 2.57 (3H, s), 3.06-3.13 (2H, t, J=8.8 Hz), 3.72 (3H,s), 4.50-4.58 (2H, m), 5.84-5.88 (2H, d, J=8.8 Hz), 6.84-6.87 (2H, d,J=8.8 Hz), 6.93 (1H, s), 7.27-7.31 (2H, d, J=8.8 Hz), 7.75 (1H, s).

Example 61

Production of2-(4-methoxyphenyl)-5-propoxy-4,7,9,10-tetrahydro-[4,7]phenanthroline-1,8-dione

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Yellow Powder (Ethyl Acetate-Methanol)

Melting point: 132-133° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.03-1.10 (3H, t, J=7.4 Hz), 1.80-2.00 (2H, m),2.33-2.39 (2H, t, J=7.4 Hz), 3.70-3.80 (5H, m), 4.04-4.09 (2H, t, J=6.5Hz), 6.85 (1H, s), 6.91-6.95 (2H, d, J=8.8 Hz), 7.53-7.56 (2H, d, J=8.8Hz), 7.72-7.75 (1H, d, J=6.4 Hz), 9.94 (1H, s), 11.02-11.25 (1H, m).

Example 62

Production of2-(4-methoxyphenyl)-7-methyl-5-propoxy-4,7,9,10-tetrahydro-[4,7]phenanthroline-1,8-dione

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Yellow Powder

Melting point: 89-91° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.03-1.10 (3H, t, J=7.4 Hz), 1.82-2.00 (2H, m),2.37-2.43 (2H, t, J=7.4 Hz), 3.32 (3H, s), 3.65-3.95 (5H, m), 4.17-4.22(2H, t, J=6.5 Hz), 6.90-6.95 (2H, d, J=8.8 Hz), 7.05 (1H, s), 7.50-7.55(2H, d, J=8.8 Hz), 7.76 (1H, s), 11.14 (1H, brs).

Example 63

Production of 5-methoxy-3-(4-methoxyphenyl)-1H-[1,10]phenanthrolin-4-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Yellow Powder (Ethanol)

Melting point: 118-120° C.

¹H-NMR (DMSO-d₆) δ ppm: 3.75 (3H, s), 3.89 (3H, s), 6.93 (2H, d, J=8.6Hz), 7.00 (1H, s), 7.57 (2H, d, J=8.6 Hz), 7.63-7.68 (1H, m), 7.91 (1H,s), 8.26 (1H, d, J=8.2 Hz), 8.78 (1H, d, J=4.2 Hz), 12.23 (1H, brs).

Example 64

Production of 5-methoxy-3-thiophen-3-yl-1H-[1,10]phenanthrolin-4-onehydrochloride

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

Pale Brown Powder (Ethanol)

Melting point: 143-145° C.

¹H-NMR (DMSO-d₆) δ ppm: 3.98 (3H, s), 7.17 (1H, s), 7.59 (1H, s), 7.60(1H, s), 7.70-7.75 (1H, m), 8.20 (1H, brs), 8.33 (1H, d, J=8.3 Hz), 8.50(1H, s), 8.81-8.83 (1H, m).

Example 65

Production of 5-methoxy-3-thiophen-2-yl-1H-[1,10]phenanthrolin-4-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

Pale Brown Powder (Ethanol)

Melting point: 265-267° C.

¹H-NMR (DMSO-d₆) δ ppm: 3.94 (3H, s), 7.07-7.10 (2H, m), 7.44 (1H, d,J=6.0 Hz), 7.60 (1H, d, J=3.7 Hz), 7.61-7.71 (1H, m), 8.29 (1H, d, J=8.3Hz), 8.47 (1H, s), 8.80-8.83 (1H, m), 12.60 (1H, brs).

Example 66

Production of5-methoxy-1-methyl-3-thiophen-2-yl-1H-[1,10]phenanthrolin-4-one

The above compound was prepared in the same manner as in Example 3 usingappropriate starting material.

Brown Powder (Ethyl Acetate-n-hexane)

Melting point: 216-218° C.

¹H-NMR (DMSO-d₆) δ ppm: 3.90 (3H, s), 4.54 (3H, s), 7.08-7.13 (2H, m),7.44 (1H, d, J=5.1 Hz), 7.56-7.61 (1H, m), 7.65 (1H, d, J=3.7 Hz), 8.24(1H, d, J=8.2 Hz), 8.64 (1H, s), 8.75-8.77 (1H, m).

Example 67

Production of 9-(4-methoxyphenyl)-6-propoxy-7H-[3,7]phenanthrolin-10-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

Melting point: 250-251° C.

¹H-NMR (CDCl₃) δ ppm: 1.14-1.19 (3H, t, J=7.4 Hz), 1.98-2.07 (2H, m),3.87 (3H, s), 4.26-4.32 (2H, t, J=6.6 Hz), 6.98-7.02 (2H, d, J=8.7 Hz),7.30 (1H, s), 7.61-7.64 (2H, d, J=6.6 Hz), 8.64-8.66 (1H, d, J=6.0 Hz),9.10 (1H, s), 9.38-9.40 (1H, d, J=4.8 Hz), 9.97-9.99 (1H, d, J=5.9 Hz).

Example 68

Production of[9-(4-methoxyphenyl)-10-oxo-6-propoxy-10H-[3,7]phenanthrolin-7-yl]aceticacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.14-1.19 (3H, t, J=7.4 Hz), 1.98-2.07 (2H, m),3.87 (3H, s), 4.26-4.32 (2H, t, J=6.6 Hz), 5.47 (2H, s), 6.98-7.02 (2H,d, J=8.7 Hz), 7.30 (1H, s), 7.61-7.64 (2H, d, J=6.6 Hz), 8.64-8.66 (1H,d, J=6.0 Hz), 9.10 (1H, s), 9.38-9.40 (1H, d, J=4.8 Hz).

Example 69

Production of2-[9-(4-methoxyphenyl)-10-oxo-6-propoxy-10H-[3,7]phenanthrolin-7-yl]-N-(2-morpholin-4-ylethyl)acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting material.

Melting point: 189-192° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.06 (3H, t, J=7.4 Hz), 1.82-1.91 (2H, m),2.82-3.12 (8H, m), 3.60-3.80 (4H, m), 3.81 (3H, s), 4.14-4.20 (2H, t,J=6.8 Hz), 5.32 (2H, s), 7.00-7.03 (2H, d, J=7.8 Hz), 7.69-7.72 (2H, d,J=7.8 Hz), 7.78 (1H, s), 8.11 (1H, s), 8.20-8.30 (1H, m), 8.51-8.53 (1H,d, J=6.1 Hz) 9.19 (1H, s), 9.99-10.0 (1H, d, J=6.1 Hz).

Example 70

Production ofethyl[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate

The above compound was prepared in the same manner as in Example 31using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.96-1.02 (3H, t, J=7.4 Hz), 1.18-1.24 (3H, t,J=7.1 Hz), 1.69-1.80 (2H, m), 3.78 (3H, s), 3.94-4.00 (2H, t, J=6.7 Hz),4.12-4.21 (2H, q, J=7.1 Hz), 5.32 (2H, s), 6.94-7.04 (3H, m), 7.21-7.26(1H, m), 7.58-7.62 (2H, d, J=8.7 Hz), 8.02 (1H, s).

Example 71

Production of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]aceticacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.97-1.03 (3H, t, J=7.4 Hz), 1.72-1.87 (2H, m),3.82 (3H, s), 3.95-4.00 (2H, t, J=6.7 Hz), 5.24 (2H, s), 6.94-7.03 (3H,m), 7.20-7.26 (1H, m), 7.59-7.62 (2H, d, J=8.7 Hz), 8.02 (1H, s),12.5-13.3 (1H, br).

Example 72

Production ofN-butyl-2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

White Powder

¹H-NMR (DMSO-d₆) δ ppm: 0.81-0.87 (3H, t, J=7.1 Hz), 0.91-0.98 (3H, t,J=7.4 Hz), 1.19-1.45 (4H, m), 1.70-1.80 (2H, m), 3.02-3.09 (2H, q, 6.3Hz), 3.76 (3H, s), 3.90-3.95 (2H, t, J=6.8 Hz), 5.13 (2H, s), 6.90-6.98(3H, m), 7.15-7.20 (1H, m), 7.56-7.60 (2H, d, J=8.7 Hz), 7.90 (1H, s),7.97-8.01 (1H, t, J=5.5 Hz).

Example 73

Production of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide

To a DMF solution (2 ml) of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]aceticacid (800 mg, 2.07 mmol) were sequentially added a DMF solution (1 ml)of 4-(2-aminoethyl)morpholine (273 mg), triethylamine (506 mg, 5.0mmol), diethylphosphorocyanidate (DEPC, 405 mg, 2.48 mmol) and DMF (1ml) while ice-cooling, followed by stirring at room temperature for 23hours. Water was added to the reaction mixture and then subjected toextraction using ethyl acetate. The thus-obtained organic layer waswashed with an aqueous saturated sodium chloride solution twice, driedover anhydrous sodium sulfate and then concentrated under reducedpressure. The residue was purified using silica gel columnchromatography (dichloromethane:methanol=30:1→15:1). The purifiedproduct was concentrated under reduced pressure, and the residue wasrecrystallized from ethyl acetate, giving a white powder of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide(789 mg, yield: 77%).

Melting point: 139-141° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.95 (3H, t, J=7.3 Hz), 1.71-1.80 (2H, m),2.30-2.34 (6H, m), 3.18 (2H, q, J=6.5 Hz), 3.49-3.53 (4H, m), 3.76 (3H,s), 3.93 (2H, t, J=6.8 Hz), 5.14 (2H, s), 6.92-6.99 (3H, m), 7.18 (1H,dd, J=4.5 Hz, 9.0 Hz), 7.58 (2H, d, J=8.8 Hz), 7.90-7.95 (2H, m).

Example 74

Production of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-methyl-N-(2-morpholin-4-ylethyl)acetamide

Sodium hydride (60% oil base, 61 mg, 1.4 mmol) was added to a DMFsolution (2 ml) of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide(580 mg, 1.16 mmol), and the resulting mixture was stirred at roomtemperature for 5 minutes. Methyl iodide (230 mg, 1.62 mmol) was addedthereto, and the thus-obtained mixture was stirred at room temperaturefor 15 hours. Water and ethyl acetate were added to the reactionmixture, followed by separation. The thus-obtained organic layer waswashed with an aqueous saturated sodium chloride solution and thenconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography (dichloromethane:methanol=30:1→15:1).The purified product was concentrated under reduced pressure, and theresidue was recrystallized from ethyl acetate, giving a white powder of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-methyl-N-(2-morpholin-4-ylethyl)acetamide(440 mg, yield: 74%).

Melting point: 218-220° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.94 (3H, t, J=7.3 Hz), 1.64-1.72 (2H, m),2.33-2.38 (4H, m), 2.43-2.50 (2H, m), 2.85 (1H, s), 2.99 (2H, s), 3.37(2H, t, J=6.8 Hz), 3.44-3.48 (4H, m), 3.75 (3H, s), 3.89 (2H, t, J=6.7Hz), 5.43 (2H, s), 6.89-6.97 (3H, m), 7.12-7.17 (1H, m), 7.53-7.57 (2H,m), 7.83 (1H, s).

Example 75

Production of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(3-morpholin-4-ylpropyl)acetamide

The above compound was prepared in the same manner as in Example 73using appropriate starting material.

White Powder (Ethyl Acetate-n-hexane)

Melting point: 117-119° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.95 (3H, t, J=7.3 Hz), 1.52-1.57 (2H, m),1.71-1.79 (2H, m), 2.21-2.29 (6H, m), 3.09 (2H, q, J=5.8 Hz), 3.49-3.54(4H, m), 3.76 (3H, s), 3.93 (2H, t, J=6.8 Hz), 5.12 (2H, s), 6.92-6.99(3H, m), 7.18 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.58 (2H, d, J=8.8 Hz), 7.90(1H, s), 8.00 (1H, t, J=5.4 Hz).

Example 76

Production of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-methyl-N-(3-morpholin-4-ylpropyl)acetamide

The above compound was prepared in the same manner as in Example 74using appropriate starting material.

White Powder (Ethyl Acetate-n-hexane)

Melting point: 166-168° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.92-0.98 (3H, m), 1.65-1.71 (4H, m), 2.21-2.36(6H, m), 2.82 (1H, s), 2.98 (2H, s), 3.20-3.30 (2H, m), 3.48-3.58 (4H,m), 3.76 (3H, s), 3.90 (2H, t, J=6.8 Hz), 5.43-5.45 (2H, m), 6.90-6.98(3H, m), 7.13-7.18 (1H, m), 7.54-7.59 (2H, m), 7.86 (1H, s).

Example 77

Production of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(1-methylpiperidin-4-yl)acetamide

The above compound was prepared in the same manner as in Example 73using appropriate starting material.

Pale Yellow Powder (Ethyl Acetate-n-hexane)

Melting point: 201-203° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.95 (3H, t, J=7.3 Hz), 1.40-1.49 (2H, m),1.67-1.84 (4H, m), 1.91-2.00 (2H, m), 2.14 (3H, s), 2.69-2.73 (2H, m),3.55-3.75 (1H, m), 3.75 (3H, s), 3.93 (2H, t, J=6.7 Hz), 5.14 (2H, s),6.90-6.98 (3H, m), 7.16 (1H, dd, J=4.4 Hz, 9.0 Hz), 7.58 (2H, d, J=8.6Hz), 7.90 (1H, s), 8.03 (1H, d, J=7.3 Hz).

Example 78

Production of tert-butyl4-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetylamino}piperidine-1-carboxylate

The above compound was prepared in the same manner as in Example 73using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.03 (3H, t, J=7.3 Hz), 1.31-1.38 (2H, m), 1.41(9H, s), 1.80-1.86 (4H, m), 2.70-3.00 (2H, m), 3.79 (3H, s), 3.88-4.13(5H, m), 4.94 (2H, s), 6.55 (1H, brs), 6.77-6.92 (4H, m), 7.31 (1H, s),7.46 (2H, d, J=8.8 Hz).

Example 79

Production of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-piperidin-4-ylacetamide

A 4N hydrochloric acid ethyl acetate solution (25 ml) was added to anethanol solution (12 ml) of tert-butyl4-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetylamino}piperidine-1-carboxylate(820 mg, 1.44 mmol), followed by stirring at room temperature for 28hours. The resulting mixture was concentrated under reduced pressure.After adding an aqueous sodium bicarbonate solution to the residue toadjust the pH to 8, the residue was washed with ethyl acetate. A 2Naqueous sodium hydroxide solution was added to the water layer to adjustits pH to 11, followed by extraction using dichloromethane. Thethus-obtained organic layer was washed with an aqueous saturated sodiumchloride solution and dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The residue was recrystallized fromethanol-ethyl acetate, giving a white powder of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-piperidin-4-ylacetamide(185 mg, yield: 27%).

Melting point: 226-228° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.94 (3H, t, J=7.3 Hz), 1.22-1.33 (2H, m),1.62-1.81 (4H, m), 2.36-2.45 (2H, m), 2.84-2.89 (2H, m), 3.55-3.75 (2H,m), 3.75 (3H, s), 3.92 (2H, t, J=6.7 Hz), 5.13 (2H, s), 6.90-6.98 (3H,m), 7.16 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.56 (2H, d, J=8.6 Hz), 7.88 (1H,s), 8.01 (1H, d, J=7.5 Hz).

Example 80

Production of ethyl4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butyrate

The above compound was prepared in the same manner as in Example 31using appropriate starting materials.

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.06 (3H, t, J=7.4 Hz), 1.06-1.12 (3H, t,J=7.13), 1.80-2.02 (4H, m), 2.24-2.30 (2H, t, J=7.4 Hz), 3.77 (3H, s),3.92-4.00 (2H, q, J=7.1 Hz), 4.03-4.09 (2H, t, J=6.6 Hz), 4.54-4.60 (2H,t, J=6.87 Hz), 6.93-7.04 (3H, m), 7.24-7.29 (1H, m), 7.60-7.63 (2H, d,J=8.6 Hz), 7.97 (1H, s).

Example 81

Production of4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butyricacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.06 (3H, t, J=7.4 Hz), 1.78-2.00 (4H, m),2.16-2.22 (2H, t, J=7.4 Hz), 3.78 (3H, s), 4.04-4.09 (2H, t, J=6.6 Hz),4.54-4.60 (2H, t, J=7.0 Hz), 6.93-7.04 (3H, m), 7.24-7.30 (1H, m),7.60-7.64 (2H, d, J=8.8 Hz), 7.97 (1H, s), 11.80-12.20 (1H, br).

Example 82

Production ofN-butyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butylamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Yellow Amorphous

¹H-NMR (DMSO-d₆) δ ppm: 0.78-0.84 (3H, t, J=7.1 Hz), 0.99-1.05 (3H, t,J=7.4 Hz), 1.10-1.42 (4H, m), 1.75-2.01 (6H, m), 2.92-2.97 (2H, m), 3.77(3H, s), 4.03-4.08 (2H, t, J=6.6 Hz), 4.53-4.58 (2H, t, J=6.2 Hz),6.92-7.03 (3H, m), 7.23-7.28 (1H, m), 7.60-7.63 (2H, t, J=8.6 Hz),7.70-7.75 (1H, m), 7.93 (1H, s).

Example 83

Production of1-(3-bromopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 17using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.12 (3H, m), 1.85-1.96 (2H, m), 2.30-2.35(2H, m), 3.33 (2H, t, J=6.1 Hz), 3.83 (3H, s), 3.96-4.05 (2H, m), 4.69(2H, t, J=6.5 Hz), 6.85-7.03 (4H, m), 7.59-7.64 (3H, m).

Example 84

Production of1-(3-chloropropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 17using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.13 (3H, m), 1.87-1.96 (2H, m), 2.22-2.27(2H, m), 3.49 (2H, t, J=5.8 Hz), 3.83 (3H, s), 3.96-4.05 (2H, m), 4.70(2H, t, J=6.5 Hz), 6.86-7.02 (4H, m), 7.59-7.64 (3H, m).

Example 85

Production of5-fluoro-3-(4-methoxyphenyl)-1-(3-morpholin-4-ylpropyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting material.

White Powder (Ethyl Acetate-n-hexane)

Melting point: 130-132° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.3 Hz), 1.73-1.87 (4H, m),2.07-2.20 (6H, m), 3.36-3.39 (4H, m), 3.74 (3H, s), 4.01 (2H, t, J=6.5Hz), 4.56 (2H, t, J=6.3 Hz), 6.90-7.00 (3H, m), 7.21 (1H, dd, J=4.5 Hz,9.0 Hz), 7.57 (2H, d, J=8.7 Hz), 7.98 (1H, s).

Example 86

Production of1-(3-diethylaminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

White Powder (Diethyl Ether)

Melting point: 80-82° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.81 (6H, t, J=7.0 Hz), 1.01 (3H, t, J=7.3 Hz),1.75-1.87 (4H, m), 2.22-2.38 (6H, m), 3.75 (3H, s), 4.03 (2H, t, J=6.6Hz), 4.54 (2H, t, J=6.7 Hz), 6.91-7.01 (3H, m), 7.23 (1H, dd, J=4.5 Hz,9.0 Hz), 7.59 (2H, d, J=8.8 Hz), 7.96 (1H, s).

Example 87

Production of5-fluoro-3-(4-methoxyphenyl)-1-[3-(4-methylpiperazin-1-yl)propyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

White Powder (Ethyl Acetate-n-hexane)

Melting point: 152-154° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.78-1.86 (4H, m), 1.96(3H, s), 2.04-2.14 (10H, m), 3.75 (3H, s), 4.02 (2H, t, J=6.5 Hz), 4.55(2H, t, J=6.2 Hz), 6.90-7.01 (3H, m), 7.23 (1H, dd, J=4.5 Hz, 9.0 Hz),7.58 (2H, d, J=8.8 Hz), 7.97 (1H, s).

Example 88

Production of5-fluoro-3-(4-methoxyphenyl)-1-(3-piperidin-1-ylpropyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

White Powder (Ethyl Acetate-n-hexane)

Melting point: 132-134° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.3 Hz), 1.20-1.40 (6H, m),1.73-1.84 (4H, m), 2.02-2.10 (6H, m), 3.74 (3H, s), 4.00 (2H, t, J=6.4Hz), 4.53 (2H, t, J=6.2 Hz), 6.89-7.00 (3H, m), 7.20 (1H, dd, J=4.5 Hz,9.0 Hz), 7.57 (2H, d, J=8.6 Hz), 7.95 (1H, s).

Example 89

Production of1-[3-(4-ethylpiperazin-1-yl)propyl]-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Pale Yellow Powder (Ethyl Acetate-n-hexane)

Melting point: 147-149° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.80-1.00 (6H, m), 1.70-1.80 (4H, m), 2.00-2.20(12H, m), 3.75 (3H, s), 4.00-4.06 (2H, m), 4.54-4.59 (2H, m), 6.90-7.00(3H, m), 7.20-7.26 (1H, m), 7.55-7.60 (2H, m), 7.98 (1H, s).

Example 90

Production of5-fluoro-1-[3-(3-hydroxy-azetidin-1-yl)propyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-onehydrochloride

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Pale Yellow Powder (Ethyl Acetate)

Melting point: 183-185° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.3 Hz), 1.79-1.94 (4H, m),3.08-3.14 (2H, m), 3.68-3.83 (5H, m), 4.05 (2H, t, J=6.7 Hz), 4.19-4.43(3H, m), 4.54-4.60 (2H, m), 6.23 (1H, brs), 6.92-7.04 (3H, m), 7.27 (1H,dd, J=4.5 Hz, 9.0 Hz), 7.61 (2H, d, J=8.6 Hz), 8.00 (1H, s), 10.30 (1H,brs).

Example 91

Production of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-[3-(4-pyridin-2-ylpiperazin-1-yl)propyl]-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

White Powder (Ethyl Acetate-n-hexane)

Melting point: 123-125° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.79-1.89 (4H, m),2.14-2.27 (6H, m), 3.20-3.30 (4H, m), 3.74 (3H, s), 4.03 (2H, t, J=6.5Hz), 4.60 (2H, t, J=6.0 Hz), 6.58 (1H, dd, J=5.0 Hz, 6.9 Hz), 6.69 (1H,d, J=8.6 Hz), 6.90-7.02 (3H, m), 7.23 (1H, dd, J=4.4 Hz, 9.0 Hz),7.40-7.50 (1H, m), 7.58-7.61 (2H, m), 8.02-8.06 (2H, m).

Example 92

Production of5-fluoro-3-(4-methoxyphenyl)-1-[3-(4-morpholin-4-ylpiperidin-1-yl)propyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Pale Brown Powder (Ethyl Acetate)

Melting point: 168-170° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.12-1.20 (2H, m),1.50-1.55 (2H, m), 1.68-1.86 (6H, m), 1.90-2.11 (3H, m), 2.30-2.33 (4H,m), 2.62-2.67 (2H, m), 3.48-3.51 (4H, m), 3.75 (3H, s), 4.03 (2H, t,J=6.5 Hz), 4.56 (2H, t, J=5.9 Hz), 6.90-7.01 (3H, m), 7.23 (1H, dd,J=4.5 Hz, 9.0 Hz), 7.60 (2H, d, J=8.8 Hz), 7.99 (1H, s).

Example 93

Production of5-fluoro-1-{3-[4-(2-methoxyethyl)piperazin-1-yl]propyl}-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-onedihydrochloride

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Pale Beige Color Powder (Ethyl Acetate)

Melting point: 184-186° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.81-1.89 (2H, m),2.00-2.25 (2H, m), 2.80-2.97 (2H, m), 3.25 (3H, s), 3.20-3.40 (4H, m),3.60-3.65 (8H, m), 3.75 (3H, s), 4.06 (2H, t, J=6.7 Hz), 4.60 (2H, t,J=6.3 Hz), 6.91-7.04 (3H, m), 7.26 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.61 (2H,d, J=8.8 Hz), 8.03 (1H, s).

Example 94

Production of2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}isoindole-1,3-dione

Sodium hydride (60% oil base, 800 mg, 18.3 mmol) was added to a DMFsolution (25 ml) of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (5.0 g, 15.2mmol). The mixture was stirred for 30 minutes at room temperature.N-Bromopropyl phthalimide (4.48 g, 16.7 mmol) was added to the mixtureand stirred at room temperature for 30 minutes and at 50° C. for 5hours. The reaction mixture was ice-cooled and water (20 ml) and ethylacetate were added thereto, followed by stirring for 2 hours. Thegenerated insoluble matter was separated, washed with water, and thendried, giving a pale yellow powder of2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1yl]propyl}isoindole-1,3-dione(4.63 g, yield: 59%).

¹H-NMR (DMSO-d₆) δ ppm: 0.94 (3H, t, J=7.3 Hz), 1.74-1.83 (2H, m), 2.03(2H, t, J=7.4 Hz), 3.62 (2H, t, J=6.6 Hz), 3.76 (3H, s), 4.01 (2H, t,J=6.7 Hz), 4.61 (2H, t, J=7.5 Hz), 6.91-7.02 (3H, m), 7.25 (1H, dd,J=4.5 Hz, 9.0 Hz), 7.58 (2H, d, J=8.8 Hz), 7.78-7.86 (4H, m), 8.06 (1H,s).

Example 95

Production of1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Hydrazine hydrate (0.62 ml, 12.8 mmol) was added to an ethanol solution(60 ml) of2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}isoindole-1,3-dione(2.0 g, 3.88 mmol) and heated under reflux for 4 hours. The resultingmixture was concentrated under reduced pressure, a 5N aqueous sodiumhydroxide solution was added to the thus-obtained residue, and then theresulting mixture was subjected to extraction using dichloromethane. Thethus-obtained organic layer was sequentially washed with water and anaqueous saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure, givinga yellow oily1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(1.4 g, yield: 94%).

¹H-NMR (CDCl₃) δ ppm: 1.09 (3H, t, J=7.3 Hz), 1.23 (2H, brs), 1.84-1.95(4H, m), 2.69 (2H, t, J=6.8 Hz), 3.82 (3H, s), 4.01 (2H, t, J=6.7 Hz),4.61 (2H, t, J=6.9 Hz), 6.83-7.02 (4H, m), 7.59-7.65 (3H, m).

Example 96

Production of2-chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide

A dichloromethane solution (6 ml) of1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(645 mg, 1.67 mmol) was ice-cooled. Triethylamine (253 mg, 2.5 mmol) andchloroacetyl chloride (207 mg, 1.83 mmol) were added to the solution andstirred at room temperature for 2 hours. Water was added to the reactionmixture, followed by extraction using dichloromethane. The thus-obtainedorganic layer was condensed, and the residue was then purified usingsilica gel column chromatography (dichloromethane:ethylacetate=4:1→2:1). The purified product was concentrated to dryness underreduced pressure, giving a white powder of2-chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide(372 mg, yield: 48%).

¹H-NMR (CDCl₃) δ ppm: 1.10 (3H, t, J=7.3 Hz), 1.86-2.09 (4H, m), 3.33(2H, q, J=6.9 Hz), 3.83 (3H, s), 4.01 (2H, s), 4.04 (2H, t, J=6.8 Hz),4.56 (2H, t, J=6.9 Hz), 6.66 (1H, brs), 6.86-6.96 (3H, m), 7.03 (1H, dd,J=4.5 Hz, 9.0 Hz), 7.52 (1H, s), 7.61 (2H, d, J=8.8 Hz).

Example 97

Production ofN-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamidehydrochloride

2-Chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide(370 mg, 0.8 mmol) was suspended in acetonitrile (12 ml).1-(2-Methoxyethyl)piperazine (138 mg, 0.96 mmol), triethylamine (162 mg,1.6 mmol) and acetonitrile (2 ml) were added to the suspension, andstirred at 70 to 80° C. for 6 hours. The resulting mixture wasconcentrated under reduced pressure, and the residue was subjected toextraction using ethyl acetate. The extract was then sequentially washedwith water, an aqueous saturated sodium chloride solution, and anaqueous saturated sodium bicarbonate solution. The washed product wasconcentrated under reduced pressure, and the residue was purified usingsilica gel column chromatography (dichloromethane:methanol=30:1→10:1).The purified product was concentrated under reduced pressure, and theresidue was then dissolved in ethyl acetate (5 ml). A 4N hydrogenchloride ethyl acetate solution (0.19 ml) was added thereto and stirred,and then the mixture was concentrated to dryness under reduced pressure,giving a pale yellow amorphous solid ofN-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamidehydrochloride (200 mg).

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.3 Hz), 1.78-1.89 (4H, m),2.50-3.00 (4H, m), 2.96-3.20 (8H, m), 3.25 (3H, s), 3.62-3.66 (4H, m),3.75 (3H, s), 3.98-4.04 (2H, m), 4.56 (2H, t, J=6.4 Hz), 6.91-7.02 (3H,m), 7.24 (1H, dd, J=4.5 Hz, 9.1 Hz), 7.60 (2H, d, J=8.8 Hz), 8.00 (1H,s), 8.07 (1H, brs).

Example 98

Production of1-(4-bromobutyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 17using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.06-1.13 (3H, m), 1.70-2.00 (6H, m), 3.39 (2H, t,J=6.3 Hz), 3.83 (3H, s), 4.03 (2H, t, J=6.7 Hz), 4.53 (2H, t, J=6.8 Hz),6.86-7.03 (4H, m), 7.49 (1H, s), 7.57-7.63 (2H, m).

Example 99

Production of5-fluoro-3-(4-methoxyphenyl)-1-(4-morpholin-4-ylbutyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting material.

White Powder (Ethyl Acetate-n-hexane)

Melting point: 118-120° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.98 (3H, t, J=7.3 Hz), 1.27-1.35 (2H, m),1.62-1.82 (4H, m), 2.13-2.19 (6H, m), 3.44-3.47 (4H, m), 3.73 (3H, s),3.98 (2H, t, J=6.5 Hz), 4.49 (2H, t, J=6.8 Hz), 6.89-6.99 (3H, m), 7.19(1H, dd, J=4.5 Hz, 9.0 Hz), 7.57 (2H, d, J=8.6 Hz), 7.95 (1H, s).

Example 100

Production of 5-fluoro-3-(4-methoxyphenyl)-1-[4-(4-methylpiperazin-1-yl)butyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 18using appropriate starting materials.

Pale Yellow Amorphous

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.3 Hz), 1.27-1.32 (2H, m),1.62-1.65 (2H, m), 1.79 (2H, q, J=6.9 Hz), 2.07 (3H, s), 2.11-2.21 (10H,m), 3.74 (3H, s), 4.00 (2H, t, J=6.5 Hz), 4.49 (2H, t, J=6.8 Hz),6.90-7.00 (3H, m), 7.21 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.58 (2H, d, J=8.6Hz), 7.96 (1H, s).

Example 101

Production of2-{4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butyl}isoindole-1,3-dione

The above compound was prepared in the same manner as in Example 94using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.96 (3H, t, J=7.3 Hz), 1.50-1.80 (6H, m), 3.57(2H, t, J=6.3 Hz), 3.76 (3H, s), 3.97 (2H, t, J=6.7 Hz), 4.49 (2H, t,J=6.8 Hz), 6.88-6.95 (3H, m), 7.18 (1H, dd, J=4.5 Hz, 9.1 Hz), 7.60 (2H,d, J=8.7 Hz), 7.80-7.90 (4H, m), 8.01 (1H, s).

Example 102

Production of1-(4-aminobutyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 95using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.10 (3H, t, J=7.3 Hz), 1.36-1.60 (4H, m),1.75-1.95 (4H, m), 2.69 (2H, t, J=6.9 Hz), 3.82 (3H, s), 4.01 (2H, t,J=6.6 Hz), 4.50 (2H, t, J=7.3 Hz), 6.83-7.02 (4H, m), 7.50 (1H, s), 7.60(2H, d, J=8.5 Hz).

Example 103

Production of2-{6-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]hexyl}isoindole-1,3-dione

The above compound was prepared in the same manner as in Example 94using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.08 (3H, t, J=7.3 Hz), 1.20-1.77 (8H, m),1.83-1.94 (2H, m), 3.65 (2H, t, J=6.9 Hz), 3.82 (3H, s), 4.01 (2H, t,J=6.5 Hz), 4.46 (2H, t, J=7.3 Hz), 6.83-7.04 (4H, m), 7.49 (1H, s), 7.61(2H, d, J=8.7 Hz), 7.68-7.83 (4H, m).

Example 104

Production of1-(6-aminohexyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 95using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.10 (3H, t, J=7.3 Hz), 1.30-1.80 (10H, m),1.87-1.95 (2H, m), 2.65 (2H, t, J=6.4 Hz), 3.83 (3H, s), 4.01 (2H, t,J=6.6 Hz), 4.47 (2H, t, J=7.5 Hz), 6.88-7.03 (4H, m), 7.50 (1H, s), 7.62(2H, d, J=8.7 Hz).

Example 105

Production of1-(2-chloroethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 17using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, t, J=7.4 Hz), 1.81-2.01 (2H, m),3.83 (3H, s), 3.84-3.89 (2H, t, J=6.3 Hz), 4.00-4.05 (2H, t, J=6.7 Hz),4.74-4.79 (2H, t, J=6.3 Hz), 6.89-7.04 (4H, m), 7.54 (1H, s), 7.59-7.62(2H, d, J=8.8 Hz).

Example 106

Production of5-fluoro-3-(4-methoxyphenyl)-1-(2-morpholin-4-ylethyl)-8-propoxy-1H-quinolin-4-one

Potassium carbonate (2.1 g, 15.2 mmol) and 4-(2-chloroethyl)morpholinehydrochloride (1.36 g, 7.31 mmol) were added to an N-methylpyrrolidone(NMP) solution (5 ml) of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (1.0 g, 3.05mmol) and then stirred at 50 to 60° C. for 45 hours. Water and ethylacetate were added to the reaction mixture, followed by separation. Thethus-obtained organic layer was washed with an aqueous saturated sodiumchloride solution twice, and then concentrated under reduced pressure.The residue was purified using silica gel column chromatography(dichloromethane:methanol=50:1→30:1). The purified product wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethyl acetate, giving a white powder of5-fluoro-3-(4-methoxyphenyl)-1-(2-morpholin-4-ylethyl)-8-propoxy-1H-quinolin-4-one(1.01 g, yield: 75%).

Melting point: 206-208° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.3 Hz), 1.78-1.87 (2H, m),2.33-2.36 (4H, m), 2.59 (2H, t, J=5.6 Hz), 3.43-3.47 (4H, m), 3.77 (3H,s), 4.05 (2H, t, J=6.5 Hz), 4.66 (2H, t, J=5.7 Hz), 6.94-7.02 (3H, m),7.25 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.60 (2H, d, J=8.8 Hz), 7.95 (1H, s).

Example 107

Production of2-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}isoindole-1,3-dione

The above compound was prepared in the same manner as in Example 94using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.11 (3H, t, J=7.3 Hz), 1.85-2.01 (2H, m), 3.76(3H, s), 4.03-4.12 (4H, m), 4.84 (2H, t, J=5.6 Hz), 6.84-6.89 (3H, m),6.92-7.00 (1H, m), 7.56 (2H, d, J=8.6 Hz), 7.68-7.79 (5H, m).

Example 108

Production of1-(2-aminoethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 95using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.10 (3H, t, J=7.3 Hz), 1.36 (2H, brs), 1.84-1.95(2H, m), 3.10 (2H, t, J=6.0 Hz), 3.82 (3H, s), 4.01 (2H, t, J=6.7 Hz),4.54 (2H, t, J=6.1 Hz), 6.84-7.02 (4H, m), 7.60-7.64 (3H, m).

Example 109

Production oftert-butyl((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}-2-hydroxyethyl)carbamate

A DMF solution (0.5 ml) of N-(tert-butoxycarbonyl)-L-serine (174 mg,0.85 mmol), triethylamine (198 mg, 1.96 mmol), diethylphosphorocyanidate (DEPC, 176 mg, 0.97 mmol) and DMF (0.5 ml) weresequentially added to a DMF solution (1 ml) of1-(2-aminoethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(300 mg, 0.81 mmol) while ice-cooling, and stirred at room temperaturefor 20 hours. Water was added to the reaction mixture and then subjectedto extraction using ethyl acetate. The thus-obtained organic layer waswashed with an aqueous saturated sodium chloride solution twice. Thewashed product was dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography (dichloromethane:methanol=40:1→30:1).The purified product was concentrated to dryness under reduced pressure,giving a white amorphous solid oftert-butyl((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}-2-hydroxyethyl)carbamate(338 mg, yield: 75%).

¹H-NMR (CDCl₃) δ ppm: 1.09 (3H, t, J=7.3 Hz), 1.38 (9H, s), 1.87-1.95(2H, m), 3.08 (1H, brs), 3.45-3.60 (3H, m), 3.69-3.79 (1H, m), 3.76 (3H,s), 3.99 (2H, t, J=6.8 Hz), 4.34 (1H, brs), 4.64 (2H, brs), 5.87 (1H, d,J=7.9 Hz), 6.56 (1H, dd, J=8.9 Hz, 11.7 Hz), 6.73 (2H, d, J=8.7 Hz),6.91 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.36 (2H, d, J=8.7 Hz), 7.46 (1H, s),8.26 (1H, brs).

Example 110

Production oftert-butyl((S)-5-tert-butoxycarbonylamino-5-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}pentyl)carbamate

The above compound was prepared in the same manner as in Example 109using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 0.90-1.05 (4H, m), 1.12 (3H, t, J=7.3 Hz), 1.37(9H, s), 1.41 (9H, s), 1.48-1.60 (2H, m), 1.87-1.99 (2H, m), 2.80-2.90(2H, m), 3.40-3.50 (1H, m), 3.80 (3H, s), 3.91-4.24 (5H, m), 4.53 (1H,brs), 5.27-5.33 (1H, m), 5.75-5.78 (1H, m), 6.43-6.52 (1H, m), 6.84-6.90(3H, m), 7.39-7.48 (3H, m), 8.09 (1H, brs).

Example 111

Production oftert-butyl[(S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}-2-(1H-imidazol-4-yl)ethyl]carbamate

The above compound was prepared in the same manner as in Example 109using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.10 (3H, t, J=7.3 Hz), 1.39 (9H, s), 1.85-2.01(2H, m), 2.72-2.90 (2H, m), 3.50-3.60 (1H, m), 3.76 (3H, s), 3.77-3.86(1H, m), 4.02 (2H, t, J=6.7 Hz), 4.30-4.43 (2H, m), 4.82-4.88 (1H, m),5.82 (1H, brs), 6.57 (1H, s), 6.72-6.84 (3H, m), 6.94-6.99 (1H, m), 7.08(1H, s), 7.37-7.45 (3H, m), 8.05 (1H, brs).

Example 112

Production of2-chloro-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}acetamide

The above compound was prepared in the same manner as in Example 96using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.12 (3H, t, J=7.3 Hz), 1.90-1.98 (2H, m),3.64-3.70 (2H, m), 3.83 (3H, s), 3.98 (2H, s), 4.03 (2H, t, J=6.6 Hz),4.72-4.76 (2H, m), 6.51 (1H, dd, J=9.0 Hz, 11.7 Hz), 6.78 (2H, d, J=8.8Hz), 6.89 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.25-7.32 (3H, m), 8.54 (1H, brs).

Example 113

Production ofN-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-2-(4-morpholin-4-ylpiperidin-1-yl)acetamidedihydrochloride

The above compound was prepared in the same manner as in Example 97using appropriate starting materials.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.3 Hz), 1.75-1.96 (7H, m),2.50-2.80 (2H, m), 2.85-3.25 (10H, m), 3.76 (3H, s), 3.80-3.95 (4H, m),4.04 (2H, t, J=6.5 Hz), 4.69 (2H, brs), 6.93-7.02 (3H, m), 7.25 (1H, dd,J=4.5 Hz, 9.1 Hz), 7.64 (2H, d, J=8.8 Hz), 7.87 (1H, s), 8.69 (1H, brs).

Example 114

Production ofN-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamidedihydrochloride

The above compound was prepared in the same manner as in Example 97using appropriate starting materials.

¹H-NMR (DMSO-d₆) δ ppm: 0.98 (3H, t, J=7.3 Hz), 1.76-1.85 (2H, m),2.95-3.05 (4H, m), 3.25 (3H, s), 3.10-3.30 (2H, m), 3.39-3.64 (10H, m),3.75 (3H, s), 4.02 (2H, t, J=6.5 Hz), 4.68 (2H, brs), 6.91-7.01 (3H, m),7.23 (1H, dd, J=4.5 Hz, 9.1 Hz), 7.59 (2H, d, J=8.7 Hz), 7.86 (1H, s),8.57 (1H, t, J=5.4 Hz).

Example 115

Production of(S)-2-amino-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-hydroxypropionamidehydrochloride

A 4N hydrogen chloride ethyl acetate solution (5 ml) was added to anethanol solution (5 ml) oftert-butyl((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}-2-hydroxyethyl)carbamate(330 mg, 0.6 mmol) and stirred at room temperature for 14 hours. Theresulting mixture was concentrated under reduced pressure. Water wasadded to the residue, which was then washed with ethyl acetate. A 2Naqueous sodium hydroxide solution (6 ml) was added to the water layer toadjust its pH to 11, followed by extraction with dichloromethane. Thethus-obtained organic layer was washed with an aqueous saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography (dichloromethane:methanol=20:1→15:1).The purified product was concentrated under reduced pressure, theresidue was dissolved in ethanol (3 ml) and ethyl acetate (3 ml), and a4N hydrogen chloride ethylacetate solution (0.1 ml) was then addedthereto. The mixture was stirred and concentrated to dryness underreduced pressure, and recrystallized from ethyl acetate, giving a whitepowder of(S)-2-amino-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-hydroxypropionamidehydrochloride (145 mg, yield: 50%).

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.3 Hz), 1.76-1.88 (2H, m),3.23-3.50 (5H, m), 3.75 (3H, s), 4.05 (2H, t, J=6.5 Hz), 4.53-4.73 (2H,m), 5.40-5.42 (1H, m), 6.91-7.03 (3H, m), 7.26 (1H, dd, J=4.5 Hz, 9.0Hz), 7.58 (2H, d, J=8.7 Hz), 7.80 (1H, s), 8.00 (2H, brs), 8.58 (1H, t,J=5.2 Hz).

Example 116

Production of (S)-2,6-diaminohexanoic{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}amidedihydrochloride

The above compound was prepared in the same manner as in Example 115using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.3 Hz), 1.00-1.50 (6H, m),1.77-1.86 (2H, m), 2.57 (2H, t, J=7.2 Hz), 3.32-3.44 (3H, m), 3.50-3.70(4H, m), 3.74 (3H, s), 4.00-4.05 (2H, m), 4.53-4.82 (2H, m), 6.91-7.03(3H, m), 7.24 (1H, dd, J=4.5 Hz, 9.1 Hz), 7.60 (2H, d, J=8.7 Hz), 7.86(1H, s), 8.61 (1H, brs).

Example 117

Production of(S)-2-amino-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-(1H-imidazol-4-yl)propionamide

The above compound was prepared in the same manner as in Example 115using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 2.26(1H, dd, J=9.3 Hz, 14.5 Hz), 2.65 (1H, dd, J=3.8 Hz, 14.5 Hz), 3.26 (1H,dd, J=3.8 Hz, 9.3 Hz), 3.30-3.55 (4H, m), 3.73 (3H, s), 3.98-4.05 (2H,m), 4.64 (2H, brs), 6.61 (1H, s), 6.87-7.01 (3H, m), 7.22 (1H, dd, J=4.5Hz, 9.0 Hz), 7.48 (1H, s), 7.57 (2H, d, J=8.7 Hz), 7.79 (1H, s), 8.13(1H, brs).

Example 118

Production of1-but-3-enyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 3 usingappropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.09-1.15 (3H, t, J=7.4 Hz), 1.82-2.03 (2H, m),2.38-2.64 (2H, m), 3.85 (3H, s), 4.02-4.07 (2H, t, J=6.7 Hz), 4.55-4.61(2H, t, J=7.2 Hz), 4.96-5.15 (2H, m), 5.60-5.89 (1H, m), 6.79-7.08 (4H,m), 7.49 (1H, s), 7.61-7.64 (2H, d, J=8.8 Hz).

Example 119

Production of3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionaldehyde

A dioxane (30 ml)-water (10 ml) solution of1-but-3-enyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(1.2 g, 3.15 mmol) was prepared. A 2.6-Lutidine (0.674 g, 6.29 mmol), 4%osmic acid solution (1 ml) and sodium periodate (2.69 g, 12.6 mmol) wereadded to the solution, and stirred at room temperature for 30 minutes.Water was added to the reaction mixture, then the mixture was extractedwith dichloromethane, washed with water, and then dried over anhydroussodium sulfate. The dried product was concentrated under reducedpressure, and the residue was then purified using silica gel columnchromatography (n-hexane:ethyl acetate=100:0→0:100). The purifiedproduct was concentrated to dryness under reduced pressure, giving apale yellow powder of3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionaldehyde(1.0 g, yield: 83%).

¹H-NMR (CDCl₃) δ ppm: 1.05-1.10 (3H, t, J=7.4 Hz), 1.75-1.94 (2H, m),3.04-3.92 (2H, t, J=6.6 Hz), 3.83 (3H, s), 3.99-4.04 (2H, t, J=6.8 Hz),4.76-4.81 (2H, t, J=6.6 Hz), 6.82-7.06 (4H, m), 7.49-7.68 (3H, m), 9.81(1H, s).

Example 120

Production of3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionicacid

3-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionaldehyde(1.0 g, 2.61 mmol) was dissolved in water (10 ml), tert-butyl alcohol(20 ml) and dichloromethane (20 ml). Sodium chlorite (3.2 g, 35.4 mmol),2-methyl-2-butene (19.86 gm, 283 mmol) and sodium-dihydrogenphosphatedihydrate (2 g, 2.61 mmol) were added to the resulting solution, and thesolution was stirred at room temperature for 1 hour. Water was added tothe reaction mixture, the mixture was extracted with dichloromethane,and then washed with water and dried over anhydrous sodium sulfate. Thedried product was concentrated under reduced pressure. The residue waspurified using silica gel column chromatography (dichloromethane:ethylacetate=50:50→0:100). The purified product was concentrated to drynessunder reduced pressure, giving a pale yellow powder of3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionicacid (710 mg, yield: 68%).

¹H-NMR (DMSO-d₆) δ ppm: 0.96-1.02 (3H, t, J=7.4 Hz), 1.62-1.91 (2H, m),2.75-2.80 (2H, t, J=6.9 Hz), 3.76 (3H, s), 4.01-4.07 (2H, t, J=6.6 Hz),4.69-4.75 (2H, t, J=7.0 Hz), 6.90-7.03 (3H, m), 7.22-7.29 (1H, m),7.59-7.63 (2H, d, J=8.8 Hz), 8.03 (1H, s).

Example 121

Production of3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-[3-(4-methylpiperazin-1-yl)propyl]propionamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Melting point: 191-192° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99-1.05 (3H, t, J=7.4 Hz), 1.25-1.50 (2H, m),1.75-1.90 (2H, m), 2.20-2.45 (2H, m), 2.50-3.00 (15H, m), 3.78 (3H, s),3.98-4.05 (2H, m), 4.75-5.00 (2H, m), 6.94-7.05 (3H, m), 7.26-7.40 (1H,m), 7.58-7.62 (2H, d, J=8.7 Hz), 7.88-7.92 (2H, m).

Example 122

Production of 2-(4-methylpiperazin-1-yl)ethyl3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionatedihydrochloride

1-(2-Hydroxyethyl)-4-methylpiperazine (199 mg, 1.38 mmol),dicyclohexylcarbodiimide (310 mg, 1.50 mmol) and 4-dimethylaminopyridine(168 mg, 1.38 mmol) were added to a DMF solution (10 ml) of3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionicacid (500 mg, 1.25 mmol) and stirred overnight at room temperature.Water was added to the reaction mixture, the mixture was extracted withdichloromethane and washed with water and then dried over anhydroussodium sulfate. The dried product was concentrated under reducedpressure, and the resulting residue was purified using silica gel columnchromatography (ethyl acetate→dichloromethane:methanol=10:1). Theresidue was dissolved in ethyl acetate and a 4N hydrogen chlorideethylacetate solution was added thereto and stirred. The mixture wasconcentrated to dryness under reduced pressure, giving a pale yellowpowder of 2-(4-methyl piperazin-1-yl)ethyl3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionatedihydrochloride (110 mg, yield: 17%).

Melting point: 150-152° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99-1.05 (3H, t, J=7.4 Hz), 1.69-1.88 (2H, m),2.78 (3H, s), 2.87-3.04 (2H, m), 3.10-3.60 (10H, m), 3.77 (3H, s),4.01-4.11 (2H, t, J=6.8 Hz), 4.27-4.44 (2H, m), 4.67-4.94 (2H, m),6.76-7.09 (3H, m), 7.16-7.33 (1H, m), 7.58-7.63 (2H, d, J=8.8 Hz), 8.07(1H, s).

Example 123

Production ofS-(2-dimethylaminoethyl)3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]thiopropionatehydrochloride

The above compound was prepared in the same manner as in Example 122using appropriate starting material.

Melting point: 50-52° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.97-1.03 (3H, t, J=7.4 Hz), 1.65-1.88 (2H, m),2.68 (3H, s), 2.70 (3H, s), 2.93-3.10 (2H, m), 3.11-3.29 (4H, m), 3.76(3H, s), 4.04-4.09 (2H, t, J=6.6 Hz), 4.68-4.94 (2H, m), 6.90-7.06 (3H,m), 7.26-7.31 (1H, m), 7.61-7.64 (2H, d, J=8.7 Hz), 8.00 (1H, s),10.41-10.92 (1H, br).

Example 124

Production of1-(2-bromoethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 17using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.09-1.15 (3H, t, J=7.4 Hz), 1.82-2.03 (2H, m),3.67-3.72 (2H, t, J=6.8 Hz), 3.84 (3H, s), 4.01-4.07 (2H, t, J=6.8 Hz),4.79-4.85 (2H, t, J=6.8 Hz), 6.88-7.06 (4H, m), 7.53 (1H, s), 7.58-7.63(2H, m).

Example 125

Production of methyl3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate

1-(2-Chloroethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(3.5 g, 8.98 mmol), methyl 3-mercaptopropionate (1.19 g, 9.88 mmol), andsodium iodide (1.48 g, 9.88 mmol) were added to DMF (30 ml) and stirredat 80° C. for 5 hours. Water and ethyl acetate were added to thereaction mixture, followed by separation. The thus-obtained organiclayer was washed with water, dried over anhydrous magnesium sulfate, andthen concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography (dichloromethane). The purified productwas concentrated to dryness under reduced pressure, giving a pale yellowpowder of methyl3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate(3.2 g, yield: 75%).

¹H-NMR (DMSO-d₆) δ ppm: 0.99-1.05 (3H, t, J=7.4 Hz), 2.65-2.80 (2H, m),2.54-2.60 (2H, t, J=7.2 Hz), 2.70-2.76 (2H, t, J=7.2 Hz), 2.88-2.93 (2H,t, J=6.9 Hz), 3.56 (3H, s), 3.78 (3H, s), 4.03-4.09 (2H, t, J=6.6 Hz),4.68-4.74 (2H, t, J=6.9 Hz), 6.85-7.08 (3H, m), 7.25-7.30 (1H, m),7.52-7.67 (2H, m), 8.06 (1H, s).

Example 126

Production of3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionicacid

Lithium hydroxide mono-hydrate (31 mg, 0.74 mmol) and water (5 ml) wereadded to an acetonitrile solution (10 ml) of methyl3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate(175 mg, 0.37 mmol), and the mixture was stirred at room temperature for2 hours. The reaction mixture was washed with ethyl acetate, and then 2Nhydrochloric acid was added to the water layer to make the mixtureacidic. The generated insoluble matter was separated, washed with waterand then dried, giving a white powder of3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionicacid (140 mg, yield: 82%).

¹H-NMR (DMSO-d₆) δ ppm: 0.96-1.02 (3H, t, J=7.4 Hz), 1.70-1.90 (2H, m),2.42-2.47 (2H, t, J=7.0 Hz), 2.64-2.70 (2H, t, J=7.0 Hz), 2.85-2.90 (2H,t, J=6.8 Hz), 3.74 (3H, s), 3.99-4.04 (2H, t, J=6.6 Hz), 4.65-4.70 (2H,t, J=6.8 Hz), 6.91-7.02 (3H, m), 7.20-7.26 (1H, m), 7.55-7.60 (2H, m),8.01 (1H, s), 11.35-12.84 (1H, br).

Example 127

Production of3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionicacid

3-{2-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionicacid (2.26 g, 4.92 mmol) was dissolved in a mixed solvent ofdichloromethane (100 ml) and methanol (20 ml), m-chloroperbenzoic acid(mCPBA, purity: 70%, 2.55 g, 10.33 mmol) was added thereto, and themixture was then stirred at room temperature for 1 hour. The resultingreaction mixture was ice-cooled. An aqueous saturated sodium hydrogensulfite solution (50 ml) was added to the reaction mixture, followed byextraction with dichloromethane. The thus-obtained organic layer waswashed with water and then concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography(dichloromethane:methanol=100:0→100:10). The purified product wasconcentrated under reduced pressure and subjected to recrystallizationfrom ethyl acetate-n-hexane, giving a pale yellow powder of3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionicacid (2.2 g, yield: 91%).

¹H-NMR (DMSO-d₆) δ ppm: 0.97-1.03 (3H, t, J=7.4 Hz), 1.73-1.96 (2H, m),2.64-2.70 (2H, t, J=7.7 Hz), 3.37-3.43 (2H, t, J=7.7 Hz), 3.66-3.72 (2H,t, J=6.7 Hz), 3.77 (3H, s), 4.05-4.11 (2H, t, J=6.8 Hz), 4.94-4.99 (2H,t, J=6.7 Hz), 6.93-7.06 (3H, m), 7.27-7.30 (1H, m), 7.59-7.63 (2H, m),8.02 (1H, s).

Example 128

Production of methyl3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionate

The above compound was prepared in the same manner as in Example 127using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, t, J=7.4 Hz), 1.84-2.03 (2H, m),2.84-2.89 (2H, t, J=7.0 Hz), 3.27-3.33 (2H, t, J=7.0 Hz), 3.51-3.57 (2H,t, J=6.9 Hz), 3.70 (3H, s), 3.83 (3H, s), 4.05-4.09 (2H, t, J=6.8 Hz),4.95-5.00 (2H, t, J=6.9 Hz), 6.86-6.94 (3H, m), 7.01-7.08 (1H, m),7.58-7.64 (2H, m), 7.66 (1H, s).

Example 129

Production of5-fluoro-1-[2-(3-hydroxypropylsulfanyl)ethyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 125using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, t, J=7.4 Hz), 1.60-1.75 (2H, m),1.84-2.03 (2H, m), 2.40-2.60 (2H, m), 2.84-2.89 (2H, m), 3.60-3.75 (2H,m), 3.70 (3H, s), 4.05-4.09 (2H, t, J=6.8 Hz), 4.62-4.80 (2H, m),6.86-6.94 (3H, m), 7.01-7.08 (1H, m), 7.58-7.64 (2H, m), 7.66 (1H, s).

Example 130

Production of5-fluoro-1-[2-(3-hydroxypropane-1-sulfonyl)ethyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 127using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.97-1.03 (3H, t, J=7.4 Hz), 1.66-1.94 (4H, m),3.38-3.53 (2H, m), 3.56-3.71 (2H, m), 3.77 (3H, s), 4.03-4.14 (4H, m),4.67-4.70 (1H, t, J=5.1 Hz), 4.93-4.99 (2H, t, J=6.7 Hz), 6.93-7.06 (3H,m), 7.26-7.33 (1H, m), 7.59-7.62 (2H, m), 8.01 (1H, s).

Example 131

Production of3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionaldehyde

O-iodoxybenzoic acid (IBX, 1.9 g, 6.78 mmol) was added to a dimethylsulfoxide (DMSO) solution (3 ml) of5-fluoro-1-[2-(3-hydroxypropane-1-sulfonyl)ethyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(2.7 g, 5.65 mmol) and stirred overnight at room temperature. Water andethyl acetate were added to the reaction mixture. Subsequently,insoluble matter was filtered off, and the filtrate was then separated.The thus-obtained organic layer was washed with water and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography (n-hexane:ethyl acetate=2:1→0:1). The purified materialwas concentrated to dryness under reduced pressure, giving a whitepowder of3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionaldehyde(1.8 g, yield: 67%).

¹H-NMR (DMSO-d₆) δ ppm: 0.97-1.03 (3H, t, J=7.4 Hz), 1.82-2.03 (2H, m),2.80-3.01 (2H, m), 3.45-3.50 (2H, m), 3.60-3.70 (2H, m), 3.78 (3H, s),4.03-4.09 (2H, t, J=6.8 Hz), 4.90-5.10 (2H, m), 6.93-7.06 (3H, m),7.26-7.33 (1H, m), 7.59-7.62 (2H, m), 8.01 (1H, s), 9.67 (1H, s).

Example 132

Production of1-[2-(2-dimethylaminoethylsulfanyl)ethyl]-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-onehydrochloride

The above compound was prepared in the same manner as in Example 125using appropriate starting material.

Melting point: 93-95° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99-1.05 (3H, t, J=7.4 Hz), 1.69-1.94 (2H, m),2.69 (3H, s), 2.71 (3H, s), 2.85-3.04 (4H, m), 3.11-3.28 (2H, m), 3.76(3H, s), 4.03-4.08 (2H, t, J=6.8 Hz), 4.64-4.87 (2H, m), 6.73-7.09 (3H,m), 7.12-7.34 (1H, m), 7.63-7.67 (2H, d, J=8.8 Hz), 8.14 (1H, s),10.62-11.04 (1H, br).

Example 133

Production of 5-fluoro-3-(4-methoxyphenyl)-1-{2-[3-(4-methylpiperazin-1-yl)-3-oxo-propane-1-sulfonyl]ethyl}-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Melting point: 85-88° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.97-1.03 (3H, t, J=7.4 Hz), 1.78-1.96 (2H, m),2.25 (3H, s), 2.29-2.45 (4H, m), 2.75-2.80 (2H, t, J=7.4 Hz), 3.30-3.50(6H, m), 3.65-3.70 (2H, t, J=6.7 Hz), 4.05-4.11 (2H, t, J=6.7 Hz),4.95-5.00 (2H, t, J=6.7 Hz), 6.91-7.06 (3H, m), 7.27-7.32 (1H, m),7.60-7.64 (2H, d, J=8.8 Hz), 8.03 (1H, s).

Example 134

Production of5-fluoro-3-(4-methoxyphenyl)-1-{2-[3-(4-methylpiperazin-1-yl)propane-1-sulfonyl]ethyl}-8-propoxy-1H-quinolin-4-onedihydrochloride

N-methylpiperazine (0.455 mg, 4.54 mmol) was added to a methanolsolution (20 ml) of3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionaldehyde(1.8 g, 3.79 mmol) while ice-cooling, and then the resulting mixture wasstirred at room temperature for 1 hour. Sodium cyanoborohydride (0.238g, 3.79 mmol) and acetic acid (2 ml) were added to the resulting mixtureand stirred at room temperature for 3 hours. Water was added to thereaction mixture, then the mixture was subjected to extraction usingethyl acetate. The extract was washed with an aqueous saturated sodiumbicarbonate solution and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography(dichloromethane:methanol=100:0→10:1). The purified product wasconcentrated under reduced pressure, and a 4N hydrogen chlorideethylacetate solution was added to an ethyl acetate solution of theresidue. The thus-generated insoluble matter was separated, giving ayellow powder of5-fluoro-3-(4-methoxyphenyl)-1-{2-[3-(4-methylpiperazin-1-yl)propane-1-sulfonyl]ethyl}-8-propoxy-1H-quinolin-4-onedihydrochloride (360 mg, yield: 15%).

Melting point: 72-74° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.98-1.04 (3H, t, J=7.4 Hz), 1.78-1.96 (2H, m),2.12-2.34 (2H, m), 2.80 (3H, s), 3.00-3.75 (14H, m), 3.77 (3H, s),4.06-4.12 (2H, t, J=6.7 Hz), 4.98-5.03 (2H, t, J=6.4 Hz), 6.94-7.07 (3H,m), 7.28-7.33 (1H, m), 7.61-7.64 (2H, d, J=8.8 Hz), 8.05 (1H, s).

Example 135

Production of8-(2-benzyloxyethoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 3.77 (3H, s), 3.87-3.90 (2H, t, J=4.3 Hz),4.35-4.38 (2H, t, J=4.3 Hz), 4.58 (2H, s), 6.80-7.00 (3H, m), 7.10-7.32(6H, m), 7.54-7.57 (2H, m), 7.79-7.82 (1H, d, J=6.2 Hz), 11.49 (1H, d,J=5.2 Hz).

Example 136

Production of5-fluoro-8-(2-hydroxyethoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one

20% palladium hydroxide/carbon (5.0 g) was added to an ethanol solution(50 ml) of8-(2-benzyloxyethoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one(6.3 g, 15.0 mmol), followed by hydrogen substitution. The mixture wasstirred at room temperature for 4 hours. After completion of thereaction, the catalyst was removed and the mixture was concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography (dichloromethane:methanol=100:0→20:1). The purifiedmaterial was concentrated to dryness under reduced pressure, giving apale yellow powder of5-fluoro-8-(2-hydroxyethoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one (5.2g, yield: 99%).

¹H-NMR (DMSO-d₆) δ ppm: 3.77 (3H, s), 3.79-3.83 (2H, t, J=4.7 Hz),4.12-4.16 (2H, t, J=4.7 Hz), 6.84-6.96 (3H, m), 7.12-7.17 (1H, m),7.53-7.57 (2H, d, J=8.8 Hz), 7.85 (1H, s).

Example 137

Production of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydro-quinolin-8-yloxy]aceticacid

The above compound was prepared in the same manner as in Example 120using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 3.80 (3H, s), 4.92 (2H, s), 6.85-6.92 (3H, m),7.11-7.16 (1H, m), 7.53-7.57 (2H, d, J=8.8 Hz), 7.80-7.82 (1H, d, J=6.2Hz), 11.46-11.49 (1H, d, J=6.0 Hz), 13.10-13.30 (1H, br).

Example 138

Production ofN-butyl-2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8-yloxy]acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Pale Brown Powder

¹H-NMR (DMSO-d₆) δ ppm: 0.84-0.90 (7.2 Hz), 1.10-1.60 (4H, m), 3.15-3.23(2H, q, J=6.5 Hz), 3.76 (3H, s), 4.66 (2H, s), 6.87-6.96 (3H, m),7.11-7.16 (1H, m), 7.55-7.59 (2H, d, J=8.5 Hz), 8.31-8.35 (1H, t, 5.8Hz), 11.68 (1H, brs).

Example 139

Production of2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydro-quinolin-8-yloxy]-N-(2-morpholin-4-ylethyl)acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting material.

Melting point: 180-182° C.

¹H-NMR (DMSO-d₆) δ ppm: 2.40-2.50 (2H, m), 3.10-3.14 (2H, m), 4.45 (2H,s), 3.28-3.54 (4H, m), 3.75 (3H, s), 3.80-4.21 (4H, m), 6.84-6.95 (3H,m), 7.10-7.15 (1H, m), 7.51-7.54 (2H, d, J=8.8 Hz), 8.20-8.50 (1H, m).

Example 140

Production of ethyl4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8-yloxy]butyrate

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.22-1.27 (3H, t, J=7.1 Hz), 2.16-2.26 (2H, m),2.54-2.59 (2H, t, J=6.6 Hz), 3.81 (3H, s), 4.10-4.20 (4H, m), 6.75-6.94(4H, m), 7.55-7.72 (2H, m), 7.72-7.75 (1H, d, J=6.1 Hz), 9.49-9.51 (1H,d, J=5.2 Hz).

Example 141

Production of4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydro-quinolin-8-yloxy]butyricacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.89-2.01 (2H, m), 2.42-2.45 (2H, m), 3.69 (3H,s), 4.05-4.10 (2H, t, J=6.1 Hz), 6.76-6.89 (3H, m), 7.02-7.07 (1H, m),7.45-7.49 (2H, d, J=8.5 Hz), 7.71-7.73 (1H, d, J=5.4 Hz), 11.21-11.23(1H, d, J=4.9 Hz), 11.6-12.5 (1H, br).

Example 142

Production ofN-butyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8-yloxy]butylamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

White Amorphous

¹H-NMR (DMSO-d₆) δ ppm: 0.79-0.86 (3H, t, J=7.1 Hz), 1.15-1.40 (4H, m),2.00-2.10 (2H, m), 2.29-2.35 (2H, t, J=7.3 Hz), 2.99-3.10 (2H, m), 3.76(3H, s), 4.10-4.15 (2H, t, J=6.2 Hz), 6.84-6.95 (3H, m), 7.10-7.16 (1H,m), 7.52-7.56 (2H, t, J=8.6 Hz), 7.70-7.85 (2H, m), 11.27 (1H, brs).

Example 143

Production of4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydro-quinolin-8-yloxy]-N-(2-morpholin-4-ylethyl)butylamidehydrochloride

The above compound was prepared in the same manner as in Example 33using appropriate starting material.

Melting point: 180-182° C.

¹H-NMR (DMSO-d₆) δ ppm: 2.02-2.07 (2H, m), 2.40-2.43 (2H, m), 2.94-3.26(6H, m), 3.28-3.54 (4H, m), 3.75 (3H, s), 3.80-4.21 (4H, m), 6.84-6.95(3H, m), 7.10-7.15 (1H, m), 7.51-7.54 (2H, d, J=8.8 Hz), 8.20-8.50 (1H,m), 10.60-11.10 (1H, br).

Example 144

Production of3-[4-(2-benzyloxyethoxy)phenyl]-5-fluoro-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.03-1.09 (3H, t, J=7.4 Hz), 1.80-1.91 (2H, m),3.81-3.85 (2H, m), 4.03-4.08 (2H, t, J=6.6 Hz), 4.63 (2H, s), 6.79-6.93(4H, m), 7.30-7.37 (5H, m), 7.53-7.57 (2H, m), 7.69-7.72 (1H, d, J=6.1Hz), 9.05-9.08 (1H, d, J=5.7 Hz).

Example 145

Production of5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 136using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.06-1.09 (3H, t, J=7.4 Hz), 1.81-1.90 (2H, m),3.70-3.75 (2H, m), 3.99-4.03 (2H, m), 4.09-4.14 (2H, t, J=6.4 Hz),4.80-4.93 (1H, m), 6.86-6.97 (3H, m), 7.13-7.18 (1H, m), 7.53-7.57 (2H,d, J=8.7 Hz), 7.79-7.87 (1H, m), 11.0-11.5 (1H, m).

Example 146

Production ofethyl[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate

Ethyl[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate(4.0 g, 9.6 mmol) was dissolved in dichloromethane (20 ml). A 1M-borontribromide dichloromethane solution (35 ml, 35 mmol) was added dropwiseto the dissolution at −10° C. After stirring at the same temperature for2 hours, water was added to the reaction mixture, followed by extractionwith dichloromethane. The thus-obtained organic layer was concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography (dichloromethane:methanol=50:1→15:1). The purifiedproduct was concentrated to dryness under reduced pressure, giving ayellow powder ofethyl[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate(2.7 g, yield: 57%).

¹H-NMR (DMSO-d₆) δ ppm: 0.97 (3H, t, J=7.3 Hz), 1.19 (3H, t, J=7.1 Hz),1.69-1.77 (2H, m), 3.95 (2H, t, J=6.6 Hz), 4.14 (2H, q, J=7.1 Hz), 5.29(2H, s), 6.76 (2H, d, J=8.7 Hz), 6.97 (1H, dd, J=9.0 Hz, 11.7 Hz), 7.21(1H, dd, J=4.5 Hz, 9.0 Hz), 7.45 (2H, d, J=8.7 Hz), 7.95 (1H, s), 9.41(1H, s).

Example 147

Production of[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]aceticacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.98 (3H, t, J=7.4 Hz), 1.73-1.82 (2H, m), 3.95(2H, t, J=6.6 Hz), 5.21 (2H, s), 6.76 (2H, d, J=8.7 Hz), 6.96 (1H, dd,J=9.0 Hz, 11.6 Hz), 7.20 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.45 (2H, d, J=8.7Hz), 7.95 (1H, s), 9.40 (1H, s), 12.50 (1H, brs).

Example 148

Production of2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide

4-(2-Aminoethyl)morpholine (184 mg, 1.41 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC, 295mg, 1.54 mmol) and 1-hydroxybenzotriazole (HOBT, 215 mg, 1.41 mmol) wereadded to a DMF solution (7 ml) of[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]aceticacid (500 mg, 1.34 mmol) and then the mixture was stirred at roomtemperature for 23 hours. Water and triethylamine were added to thereaction mixture to make the reaction mixture basic, followed byextraction using ethyl acetate. The thus-obtained organic layer waswashed with an aqueous saturated sodium chloride solution, and thenconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography (dichloromethane:methanol=30:1→10:1).The purified product was concentrated under reduced pressure, and theresidue was recrystallized from ethyl acetate, giving a white powder of2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide(157 mg, yield: 24%).

¹H-NMR (DMSO-d₆) δ ppm: 0.94 (3H, t, J=7.3 Hz), 1.70-1.78 (2H, m),2.29-2.33 (6H, m), 3.17 (2H, q, J=6.3 Hz), 3.44-3.52 (4H, m), 3.92 (2H,t, J=6.8 Hz), 5.12 (2H, s), 6.75 (2H, d, J=8.7 Hz), 6.94 (1H, dd, J=8.9Hz, 11.6 Hz), 7.16 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.44 (2H, d, J=8.6 Hz),7.83 (1H, s), 7.91 (1H, t, J=5.4 Hz), 9.50 (1H, s).

Example 149

Production ofethyl(4-{5-fluoro-1-[(2-morpholin-4-ylethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetate

Potassium carbonate (129 mg, 0.93 mmol) and ethyl bromoacetate (114 mg,0.68 mmol) were added to a DMF solution (4 ml) of2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide(300 mg, 0.62 mmol), followed by stirring at room temperature for 87hours. Water and ethyl acetate were added to the reaction mixture andthe reaction mixture was then subjected to separation. The thus-obtainedorganic layer was washed with an aqueous saturated sodium chloridesolution, and then concentrated under reduced pressure. The residue waspurified using silica gel column chromatography(dichloromethane:methanol=50:1→20:1). The purified product wasconcentrated under reduced pressure, giving a pale yellow oily substanceof ethyl[(4-{5-fluoro-1-[(2-morpholin-4-ylethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetate(306 mg, yield: 87%).

¹H-NMR (CDCl₃) δ ppm: 1.02 (3H, t, J=7.3 Hz), 1.30 (3H, t, J=7.1 Hz),1.79-1.88 (2H, m), 2.30-2.43 (6H, m), 3.35 (2H, q, J=6.0 Hz), 3.48-3.52(4H, m), 3.91 (2H, t, J=6.9 Hz), 4.26 (2H, q, J=7.1 Hz), 4.59 (2H, s),5.00 (2H, s), 6.76-6.96 (5H, m), 7.37 (1H, s), 7.51 (2H, d, J=8.8 Hz).

Example 150

Production of2-(4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetamide

Ethyl(4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetate(300 mg) was added to a 7N ammonia-methanol solution (15 ml) and thenstirred at 70° C. for 43 hours. The mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography(dichloromethane:methanol=50:1→9:1→ethyl acetate:methanol=10:1). Thepurified product was concentrated under reduced pressure, and theresidue was recrystallized from ethyl acetate-n-hexane, giving a paleyellow powder of2-(4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetamide(100 mg, yield: 35%)

¹H-NMR (DMSO-d₆) δ ppm: 0.95 (3H, t, J=7.3 Hz), 1.72-1.81 (2H, m),2.32-2.34 (6H, m), 3.18 (2H, q, J=6.5 Hz), 3.50-3.54 (4H, m), 3.94 (2H,t, J=6.8 Hz), 4.43 (2H, s), 5.14 (2H, s), 6.92-7.00 (3H, m), 7.19 (1H,dd, J=4.5 Hz, 9.0 Hz), 7.39 (1H, s), 7.53 (1H, s), 7.59 (2H, d, J=8.8Hz), 7.91-7.93 (2H, brs).

Example 151

Production ofethyl(5-fluoro-4-oxo-8-propoxy-3-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-quinolin-1-yl)acetate

The above compound was prepared in the same manner as in Example 149using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.05 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.1 Hz),1.53-1.74 (6H, m), 1.80-1.88 (2H, m), 3.50-3.60 (1H, m), 3.83-3.91 (2H,m), 3.95 (2H, t, J=6.8 Hz), 4.03-4.08 (1H, m), 4.16-4.28 (4H, m), 4.72(1H, brs), 5.10 (2H, s), 6.84-7.00 (4H, m), 7.35 (1H, s), 7.58 (2H, d,J=8.8 Hz).

Example 152

Production ofethyl{5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}acetate

2N hydrochloric acid (6.3 ml) was added to an ethanol solution (20 ml)of ethyl(5-fluoro-4-oxo-8-propoxy-3-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-quinolin-1-yl)acetate(840 mg, 1.59 mmol) and stirred at 50° C. for 2 hours. The resultingmixture was cooled to room temperature and then concentrated underreduced pressure. Ethyl acetate and water were added to the residue,followed by separation. The thus-obtained organic layer was washed withan aqueous saturated sodium chloride solution, and then concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography (dichloromethane:methanol=30:1→15:1). The purifiedproduct was concentrated under reduced pressure, giving a pale yellowoily substance ofethyl{5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}acetate(627 mg, yield: 89%).

¹H-NMR (CDCl₃) δ ppm: 1.05 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.1 Hz),1.79-1.88 (3H, m), 3.92-3.98 (4H, m), 4.08-4.12 (2H, m), 4.24 (2H, q,J=7.1 Hz), 5.10 (2H, s), 6.84-7.00 (4H, m), 7.35 (1H, s), 7.58 (2H, d,J=8.8 Hz).

Example 153

Production of{5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}aceticacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.98 (3H, t, J=7.3 Hz), 1.71-1.85 (2H, m), 3.72(2H, m), 3.93-4.02 (4H, m), 4.87 (1H, brs), 5.22 (2H, s), 6.93-7.02 (3H,m), 7.22 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.57 (2H, d, J=8.8 Hz), 8.00 (1H,s), 12.50 (1H, brs).

Example 154

Production of2-{5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}-N-(2-morpholin-4-ylethyl)acetamide

The above compound was prepared in the same manner as in Example 148using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.95 (3H, t, J=7.3 Hz), 1.72-1.79 (2H, m),2.30-2.40 (6H, m), 3.18 (2H, q, J=5.9 Hz), 3.50-3.53 (4H, m), 3.69-3.74(2H, m), 3.91-4.00 (4H, m), 4.91 (1H, t, J=5.4 Hz), 5.14 (2H, s),6.92-6.98 (3H, m), 7.18 (1H, dd, J=4.4 Hz, 9.0 Hz), 7.57 (2H, d, J=8.6Hz), 7.90-7.93 (2H, brs).

Example 155

Production of ethyl4-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydro-quinolin-3-yl)phenoxy]butyrate

The above compound was prepared in the same manner as in Example 1 usingappropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, t, J=7.4 Hz), 1.25-1.31 (3H, t,J=7.1 Hz), 1.87-1.98 (2H, m), 2.10-2.17 (2H, m), 2.51-2.57 (2H, t, J=7.3Hz), 4.00-4.21 (6H, m), 6.83-6.93 (4H, m), 7.55-7.59 (2H, d, J=8.4 Hz),7.72-7.75 (1H, d, J=6.1 Hz), 8.93 (1H, brs).

Example 156

Production of4-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydro-quinolin-3-yl)phenoxy]butyricacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.93-1.00 (3H, t, J=7.4 Hz), 1.69-1.91 (4H, m),2.28-2.34 (2H, t, J=7.3 Hz), 3.89-3.94 (2H, t, J=6.4 Hz), 4.00-4.05 (2H,t, J=6.4 Hz), 6.67-6.87 (3H, m), 7.03-7.08 (1H, m), 7.43-7.47 (2H, d,J=8.7 Hz), 7.71-7.73 (1H, d, J=6.3 Hz), 11.18-11.20 (1H, d, J=6.0 Hz),11.5-12.2 (1H, br).

Example 157

Production ofN-butyl-4-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)phenoxy]butylamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

White Amorphous

¹H-NMR (DMSO-d₆) δ ppm: 0.81-0.87 (3H, t, J=7.3 Hz), 1.01-1.08 (3H, t,J=7.4 Hz), 1.20-1.40 (4H, m), 1.80-1.95 (4H, m), 2.19-2.25 (2H, t, J=7.4Hz), 3.00-3.40 (2H, m), 3.93-3.99 (2H, t, J=6.3 Hz), 4.07-4.13 (2H, t,J=6.4 Hz), 6.84-6.93 (3H, m), 7.11-7.16 (1H, m), 7.51-7.54 (2H, d, J=8.5Hz), 7.82 (2H, m), 11.24 (1H, brs).

Example 158

Production of[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)phenoxy]aceticacid

The above compound was prepared in the same manner as in Example 2 usingappropriate starting materials.

¹H-NMR (DMSO-d₆) δ ppm: 1.03-1.09 (3H, t, J=7.4 Hz), 1.78-1.92 (2H, m),4.09-4.14 (2H, t, J=6.4 Hz), 4.70 (2H, s), 6.86-6.97 (3H, m), 7.13-7.18(1H, m), 7.51-7.56 (2H, m), 7.80-7.83 (1H, d, J=6.3 Hz), 11.27-11.29(1H, d, J=6.0 Hz), 12.99 (1H, brs).

Example 159

Production ofN-butyl-2-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)phenoxy]acetamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

White Powder

¹H-NMR (DMSO-d₆) δ ppm: 0.83-0.88 (3H, t, J=7.2 Hz), 1.02-1.08 (3H, t,J=7.4 Hz), 1.23-1.50 (4H, m), 1.80-1.88 (2H, m), 3.08-3.16 (2H, m),4.08-4.13 (2H, t, J=6.4 Hz), 4.47 (2H, s), 6.85-6.97 (3H, m), 7.12-7.17(1H, m), 7.53-7.56 (2H, d, J=8.8 Hz), 7.80 (1H, s), 8.03-8.08 (1H, t,J=5.5 Hz), 11.24 (1H, brs).

Example 160

Production of4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzaldehyde

The above compound was prepared in the same manner as in Example 2 usingappropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.11 (3H, t, J=7.3 Hz), 1.86-2.00 (2H, m), 4.12(2H, t, J=6.6 Hz), 6.85-6.98 (2H, m), 7.84-7.93 (5H, m), 8.90 (1H, brs),10.02 (1H, s).

Example 161

Production of5-fluoro-3-[4-(4-morpholin-4-ylpiperidine-1-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 106using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.01 (3H, t, J=7.3 Hz), 1.74-1.86 (2H, m),2.32-2.35 (4H, m), 2.59 (2H, t, J=5.4 Hz), 3.51-3.54 (4H, m), 4.04 (2H,t, J=6.5 Hz), 4.50 (2H, d, J=4.5 Hz), 4.66 (2H, d, J=5.4 Hz), 5.22 (1H,brs), 6.99 (1H, dd, J=8.9 Hz, 11.6 Hz), 7.22-7.33 (3H, m), 7.61 (2H, d,J=8.2 Hz), 7.97 (1H, s).

Example 162

Production of4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)-N-(2-morpholin-4-ylethyl)benzamide

The above compound was prepared in the same manner as in Example 73using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.3 Hz), 1.75-1.89 (2H, m),2.38-2.50 (6H, m), 3.38 (2H, q, J=6.3 Hz), 3.53-3.61 (4H, m), 4.08 (2H,t, J=6.4 Hz), 6.92 (1H, dd, J=8.7 Hz, 12.0 Hz), 7.15 (1H, dd, J=3.9 Hz,8.8 Hz), 7.71 (2H, d, J=8.5 Hz), 7.89 (2H, d, J=8.5 Hz), 7.94 (1H, s),8.41 (1H, t, J=5.5 Hz), 11.46 (1H, brs).

Example 163

Production of5-fluoro-3-[4-(4-morpholin-4-yl-piperidine-1-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 73using appropriate starting materials.

¹H-NMR (DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.3 Hz), 1.30-1.38 (2H, m),1.75-1.89 (4H, m), 2.34-2.49 (4H, m), 2.79-3.02 (2H, m), 3.61-3.69 (6H,m), 4.08 (2H, t, J=6.4 Hz), 4.42 (1H, brs), 6.92 (1H, dd, J=8.8 Hz, 12.0Hz), 7.15 (1H, dd, J=3.9 Hz, 8.8 Hz), 7.37 (2H, d, J=8.2 Hz), 7.67 (2H,d, J=8.2 Hz), 7.92 (1H, s), 11.45 (1H, brs).

Example 164

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carbaldehyde

The above compound was prepared in the same manner as in Example 2 usingappropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.10-1.16 (3H, t, J=7.4 Hz), 1.86-2.00 (2H, m),3.86 (3H, s), 4.02-4.07 (2H, t, J=6.5 Hz), 6.72-6.91 (1H, m), 6.92-7.05(3H, m), 7.31-7.43 (2H, m), 9.25 (1H, brs), 9.77 (1H, s).

Example 165

Production of methyl5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylicacid

The above compound was prepared in the same manner as in Example 2 usingappropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.10-1.16 (3H, t, J=7.4 Hz), 1.85-2.05 (2H, m),3.70 (3H, s), 3.85 (3H, s), 4.10-4.15 (2H, t, J=6.5 Hz), 6.75-6.99 (4H,m), 7.12-7.22 (2H, m), 9.36 (1H, brs).

Example 166

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylicacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.06 (3H, t, J=7.4 Hz), 1.69-1.92 (2H, m),3.76 (3H, s), 4.10-4.15 (2H, t, J=6.5 Hz), 6.88-6.97 (3H, m), 7.12-7.23(3H, m), 10.78 (1H, brs), 13.00-15.00 (1H, br).

Example 167

Production of 2-hydroxyethyl5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboamide

Ethanolamine (10 ml) was added to methyl5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylicacid (3.2 g, 7.78 mmol) and stirred at 100° C. for 3 hours. The mixturewas cooled to room temperature and purified using silica gel columnchromatography (dichloromethane:methanol=100:0→20:1). The purifiedmaterial was concentrated to dryness under reduced pressure, giving apale yellow amorphous solid of 2-hydroxyethyl5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboamide(3.0 g, yield: 93%).

¹H-NMR (DMSO-d₆) δ ppm: 0.99-1.05 (3H, t, J=7.4 Hz), 1.69-1.95 (2H, m),2.92-3.17 (4H, m), 3.76 (3H, s), 4.08-4.13 (2H, t, J=6.6 Hz), 4.32-4.57(1H, m), 6.86-6.93 (3H, m), 7.15-7.21 (3H, m), 8.13-8.33 (1H, m), 11.09(1H, brs).

Example 168

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide

Triphenyl phosphine (2.47 g, 9.8 mmol) and carbon tetrachloride (1.4 g,9.1 mmol) were added to a THF solution (30 ml) of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydro-quinoline-2-carboxy-(2-hydroxyethyl)amide(3.0 g, 7.24 mmol) and heated under reflux for 2 hours. The mixture wascooled to room temperature, and water was then added thereto, followedby extraction with dichloromethane. The thus-obtained organic layer waswashed with water, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography (dichloromethane:methanol=100:0→20:1).The purified material was concentrated to dryness under reducedpressure, giving a white powder of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide(1.8 g, yield: 58%).

¹H-NMR (DMSO-d₆) δ ppm: 0.99-1.04 (3H, t, J=7.4 Hz), 1.75-1.89 (2H, m),3.20-3.30 (4H, m), 3.75 (3H, s), 4.08-4.13 (2H, t, J=6.6 Hz), 6.86-6.95(3H, m), 7.16-7.21 (3H, m), 8.64-8.69 (1H, t, J=5.4 Hz), 11.14 (1H, s).

Example 169

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-hydroxyethyl)methylamide

The above compound was prepared in the same manner as in Example 167using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 100-1.10 (3H, m), 1.83-1.95 (2H, m), 3.42-3.54(5H, m), 3.60-3.65 (2H, m), 3.80 (1.2H, s), 3.82 (1.8H, s), 3.99-4.00(0.8H, t, J=6.6 Hz), 4.06-4.12 (1.2H, t, J=6.6 Hz), 6.75-6.96 (4H, m),7.32-7.45 (2H, m), 8.89 (0.6H, brs), 9.31 (0.4H, brs).

Example 170

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-[2-(4-methylpiperazin-1-yl)ethyl]amide

N-methylpiperazine (276 mg, 2.76 mmol), sodium iodide (440 mg, 2.9 mmol)and potassium carbonate (572 mg, 4.14 mmol) were added to a DMF solution(8 ml) of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide(600 mg, 1.38 mmol) and stirred overnight at 80° C. The mixture wascooled to room temperature, and water was then added thereto, followedby extraction using chloroform. The thus-obtained organic layer wasconcentrated under reduced pressure, and the residue was then purifiedusing medium pressure liquid chromatography (NH silica gel,dichloromethane:methanol=100:0→10:1). The purified product wasconcentrated under reduced pressure, giving a white powder of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydro-quinoline-2-carboxy-[2-(4-methylpiperazin-1-yl)ethyl]amide(100 mg, yield: 14%).

Melting point: 106-107° C.

¹H-NMR (CDCl₃) δ ppm: 1.10-1.16 (3H, t, J=7.4 Hz), 1.90-1.99 (2H, m),2.21-2.80 (13H, m), 3.28-3.35 (2H, m), 3.85 (3H, s), 4.08-4.14 (2H, t,J=6.5 Hz), 6.25-6.50 (1H, brs), 6.79-7.05 (4H, m), 7.28-7.32 (2H, m),9.77-10.1 (1H, br).

Example 171

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-[2-(morpholin-4-yl)ethyl]amide

The above compound was prepared in the same manner as in Example 170using appropriate starting material.

Melting point: 111-112° C.

¹H-NMR (CDCl₃) δ ppm: 1.10-1.16 (3H, t, J=7.4 Hz), 1.88-2.00 (2H, m),2.17-2.25 (6H, m), 3.29-3.35 (2H, m), 3.54-3.58 (4H, m), 3.84 (3H, s),4.08-4.14 (2H, t, J=6.4 Hz), 6.35-6.50 (1H, m), 6.79-7.05 (4H, m),7.28-7.34 (2H, m), 9.96 (1H, s).

Example 172

Production of5-fluoro-2-{[(2-hydroxyethyl)methylamino]methyl}-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 134using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.13 (3H, t, J=7.4 Hz), 1.83-1.92 (2H, m),2.32 (3H, s), 2.61-2.65 (2H, t, J=5.5 Hz), 3.75-3.80 (2H, m), 3.82 (3H,s), 4.04-4.12 (3H, m), 6.72-6.94 (4H, m), 7.13-7.17 (2H, m), 10.03 (1H,brs).

Example 173

Production of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-quinolin-4-one

1-(2-Pyridyl)piperazine (551 mg, 3.38 mmol) was added to a1,2-dichloromethane solution (20 ml) of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carbaldehyde(800 mg, 2.25 mmol) and stirred at room temperature for 1 hour. Sodiumtriacetoxyborohydride (670 mg, 3.16 mmol) was added to the resultingmixture and stirred at room temperature for 4 hours. Dichloromethane wasadded to the resulting reaction mixture, washed with water, and then themixture was dried over sodium sulfate. Thereafter, the solvent wasremoved under reduced pressure. The residue was then purified using NHsilica gel column chromatography (dichloromethane:ethyl acetate=1:1).The solvent was removed under reduced pressure and the residue wasrecrystallized from ethyl acetate-n-hexane, giving a white powder of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-quinolin-4-one(400 mg, yield: 35%).

Melting point: 211-212° C.

¹H-NMR (CDCl₃) δ ppm: 1.06-1.13 (3H, t, J=7.4 Hz), 1.84-1.93 (2H, m),2.63-2.67 (4H, m), 3.50-3.65 (6H, m), 3.89 (3H, s), 4.06-4.11 (2H, t,J=6.3 Hz), 6.93-6.68 (2H, m), 6.76-6.98 (4H, m), 7.16-7.20 (2H, d, J=8.8Hz), 7.45-7.56 (1H, m), 8.18-8.21 (1H, m), 10.0-10.2 (1H, brs).

Example 174

Production of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-4-yl-piperazin-1-ylmethyl)-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 210-211° C.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.11 (3H, t, J=7.4 Hz), 1.81-1.95 (2H, m),2.66-2.70 (4H, m), 3.38-3.42 (4H, m), 3.56 (2H, s), 3.83 (3H, s),4.06-4.11 (2H, t, J=6.3 Hz), 6.66-6.69 (2H, d, J=5.3 Hz), 6.76-6.97 (4H,m), 7.15-7.19 (2H, d, J=7.5 Hz), 8.28-8.30 (2H, d, J=5.3 Hz), 9.90-10.2(1H, brs).

Example 175

Production of5-fluoro-3-(4-methoxyphenyl)-2-[4-(6-methylpyridin-2-yl)piperazin-1-ylmethyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 205-206° C.

¹H-NMR (CDCl₃) δ ppm: 1.06-1.12 (3H, t, J=7.3 Hz), 1.85-1.93 (2H, m),2.39 (3H, s), 2.62-2.64 (4H, m), 3.53 (2H, s), 3.55-3.70 (4H, m), 3.83(3H, s), 4.05-4.10 (2H, t, J=6.4 Hz), 6.41-6.44 (1H, d, J=8.4 Hz),6.50-6.53 (1H, d, J=7.3 Hz), 6.75-6.96 (4H, m), 7.16-7.20 (2H, d, J=8.8Hz), 7.37-7.41 (1H, m), 10.2 (1H, s).

Example 176

Production of5-fluoro-3-(4-methoxyphenyl)-2-[4-(2-methylpyridin-4-yl)piperazin-1-ylmethyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 205-207° C.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.11 (3H, t, J=7.4 Hz), 1.81-1.95 (2H, m),2.46 (3H, s), 2.60-2.70 (4H, m), 3.30-3.40 (4H, m), 3.54 (2H, s), 3.82(3H, s), 4.05-4.10 (2H, t, J=6.3 Hz), 6.45-6.55 (2H, m), 6.74-6.95 (4H,m), 7.13-7.17 (2H, d, J=8.7 Hz), 8.17-8.19 (1H, d, J=5.9 Hz), 10.04 (1H,s).

Example 177

Production of5-fluoro-3-(4-methoxyphenyl)-2-(4-methyl-[1,4]diazepam-1-ylmethyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 243-244° C.

¹H-NMR (CDCl₃) δ ppm: 1.13-1.20 (3H, t, J=7.4 Hz), 1.50-1.70 (2H, m),2.30-2.60 (3H, m), 2.70-2.90 (6H, m), 3.40-3.77 (4H, m), 3.83 (3H, s),4.11-4.16 (2H, t, J=6.3 Hz), 6.76-6.96 (4H, m), 7.08-7.12 (2H, d, J=8.7Hz), 9.60 (1H, s).

Example 178

Production of5-fluoro-3-(4-methoxyphenyl)-2-[(2-morpholin-4-ylethylamino)methyl]-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 135-137° C.

¹H-NMR (CDCl₃) δ ppm: 1.11-1.17 (3H, t, J=7.4 Hz), 1.87-2.15 (3H, m),2.39-2.42 (4H, m), 2.46-2.51 (2H, t, J=5.7 Hz), 2.64-2.68 (2H, t, J=5.7Hz), 3.65-3.68 (4H, t, J=4.6 Hz), 3.74 (2H, s), 3.83 (3H, s), 4.07-4.12(2H, t, J=6.3 Hz), 6.74-6.96 (4H, m), 7.16-7.20 (2H, m), 10.35 (1H, s).

Example 179

Production of5-fluoro-3-(4-methoxyphenyl)-2-{[methyl-(2-morpholin-4-ylethyl)amino]methyl}-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 127-128° C.

¹H-NMR (CDCl₃) δ ppm: 1.10-1.17 (3H, t, J=7.4 Hz), 1.86-2.00 (2H, m),2.30-2.42 (7H, m), 2.46-2.52 (2H, m), 2.58-2.64 (2H, m), 3.52 (2H, s),3.52-3.63 (4H, t, J=4.6 Hz), 3.83 (3H, s), 4.08-4.13 (2H, t, J=6.3 Hz),6.75-6.96 (4H, m), 7.13-7.18 (2H, d, J=8.7 Hz), 10.11 (1H, s).

Example 180

Production of2-{[(2-chloroethyl)methylamino]methyl}-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 168using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 100-1.10 (3H, m), 1.83-1.95 (2H, m), 2.26 (3H, s),2.64 (2H, m), 3.03 (2H, s), 3.48 2H, m), 3.82 (3H, s), 4.08-4.13 (2H, t,J=6.6 Hz), 6.75-6.96 (4H, m), 7.32-7.45 (2H, m), 8.89 (0.6H, brs), 9.31(0.4H, brs).

Example 181

Production of5-fluoro-2-hydroxymethyl-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

A dichloromethane solution (30 ml) of methyl5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylate(5.0 g, 13 mmol) was cooled to −78° C., and hydrogenateddiisobutylaluminium (DIBAL-H, 1M toluene solution, 30 ml) was addedthereto dropwise under a nitrogen atmosphere. After completion of theaddition, the mixture was stirred at the same temperature for 3 hours.The reaction mixture was heated to room temperature, and 5N sodiumhydroxide was added thereto, followed by extraction withdichloromethane. The thus-obtained organic layer was washed with water,dried over sodium sulfate, and then concentrated under reduced pressure.The residue was purified using silica gel column chromatography(dichloromethane:methanol=10:1). The purified material was concentratedto dryness under reduced pressure, giving a yellow amorphous solid of5-fluoro-2-hydroxymethyl-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(4.8 g, yield: 85%).

¹H-NMR (CDCl₃) δ ppm: 1.04-1.10 (3H, t, J=7.4 Hz), 1.83-1.92 (2H, m),3.75 (3H, s), 4.02-4.07 (2H, t, J=6.5 Hz), 4.39 (2H, s), 4.67 (1H, brs),6.71-6.83 (4H, m), 6.95-6.98 (2H, m), 9.82 (1H, s).

Example 182

Production of5-fluoro-3-(4-methoxyphenyl)-2-morpholin-4-ylmethyl-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 175-176° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.09-1.14 (3H, t, J=7.4 Hz), 1.78-1.94 (2H, m),2.32-2.47 (4H, m), 3.47 (2H, s), 3.55-3.68 (4H, m), 3.77 (3H, s),4.12-4.16 (2H, t, J=6.2 Hz), 6.79-7.00 (3H, m), 7.06-7.14 (2H, m),7.15-7.25 (1H, m), 10.21 (1H, brs).

Example 183

Production of5-fluoro-3-(4-methoxyphenyl)-2-(4-methylpiperazin-1-ylmethyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 173using appropriate starting material.

Melting point: 204-205° C.

¹H-NMR (CDCl₃) δ ppm: 1.18-1.24 (3H, t, J=7.4 Hz), 1.86-2.08 (2H, m),2.31 (3H, s), 2.36-2.79 (8H, m), 3.49 (2H, s), 3.84 (3H, s), 4.08-4.13(2H, t, J=6.2 Hz), 6.68-7.00 (4H, m), 7.11-7.22 (2H, m), 10.21 (1H,brs).

Example 184

Production of4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinolin-2-yl]butyricacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

Melting point: 154-156° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.99 (3H, t, J=7.3 Hz), 1.65-1.71 (2H, m),1.79-1.87 (2H, m), 2.09 (2H, t, J=7.4 Hz), 2.57 (2H, t, J=7.0 Hz), 3.76(3H, s), 4.13 (2H, t, J=6.6 Hz), 6.81-6.94 (3H, m), 7.06 (2H, d, J=8.7Hz), 7.14 (1H, dd, J=4.0 Hz, 8.8 Hz), 10.40 (1H, brs).

Example 185

Production ofN-butyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinolin-2-yl]butylamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Pale Yellow Powder (Diethyl Ether)

Melting point: 134-136° C.

¹H-NMR (DMSO-d₆) δ ppm: 0.82 (3H, t, J=6.9 Hz), 1.00 (3H, t, J=7.3 Hz),1.19-1.30 (4H, m), 1.64-1.70 (2H, m), 1.84 (2H, q, J=6.9 Hz), 1.98-2.03(2H, m), 2.48-2.56 (2H, m), 2.94-2.99 (2H, m), 3.75 (3H, s), 4.10 (2H,t, J=6.4 Hz), 6.81-6.93 (3H, m), 7.05-7.15 (3H, m), 7.82 (1H, t, J=5.0Hz), 10.97 (1H, brs).

Example 186

Production of 5-fluoro-8-propoxy-3-pyrimidin-5-yl-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 2 usingappropriate starting materials.

Melting point: >250° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.06 (3H, t, J=7.4 Hz), 1.75-2.00 (2H, m), 4.14(2H, t, J=6.4 Hz), 6.99 (1H, dd, J=8.8, 12.0 Hz), 7.23 (1H, dd, J=3.9,8.8 Hz), 8.12 (1H, s), 9.08 (2H, s), 9.10 (1H, s), 11.68 (1H, s).

Example 187

Production of5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 2 usingappropriate starting materials.

Melting point: 223-225° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.06 (3H, t, J=7.4 Hz), 1.75-1.95 (2H, m), 3.87(3H, s), 4.11 (2H, t, J=6.4 Hz), 6.90 (1H, dd, J=8.7, 12.0 Hz), 7.13(1H, dd, J=3.9, 8.7 Hz), 7.95 (1H, s), 8.08 (1H, d, J=5.4 Hz), 8.37 (1H,s), 11.36 (1H, d, J=5.4 Hz).

Example 188

Production of di-tert-butyl5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.11 (3H, t, J=7.4 Hz), 1.36 (18H, s), 1.85-2.05(2H, m), 3.83 (3H, s), 4.07 (2H, t, J=6.6 Hz), 6.32 (2H, d, J=13.0 Hz),6.90-7.00 (3H, m), 7.07 (1H, dd, J=4.5, 9.0 Hz), 7.63 (2H, d, J=8.9 Hz),7.79 (1H, s).

Example 189

Production of di-tert-butyl3-(2,4-dichlorophenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.11 (3H, t, J=7.4 Hz), 1.37 (18H, s), 1.85-2.05(2H, m), 4.08 (2H, t, J=6.6 Hz), 6.30 (2H, d, J=12.6 Hz), 6.99 (1H, dd,J=9.0, 10.7 Hz), 7.13 (1H, dd, J=4.4, 9.0 Hz), 7.27 (1H, dd, J=2.1, 8.3Hz), 7.37 (1H, d, J=8.3 Hz), 7.47 (1H, d, J=2.1 Hz), 7.75 (1H, s).

Example 190

Production of di-tert-butyl3-(2,4-dimethoxyphenyl)-8-ethoxy-5-fluoro-4-oxo-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.37 (18H, s), 1.54 (3H, t, J=7.0 Hz), 3.76 (3H,s), 3.83 (3H, s), 4.18 (2H, q, J=7.0 Hz), 6.28 (2H, d, J=11.9 Hz),6.50-6.60 (2H, m), 6.93 (1H, dd, J=9.0, 10.9 Hz), 7.07 (1H, dd, J=4.5,9.0 Hz), 7.34 (1H, d, J=9.0 Hz), 7.72 (1H, s).

Example 191

Production of di-tert-butyl3-(4-ethoxyphenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.11 (3H, t, J=7.5 Hz), 1.36 (18H, s), 1.42 (3H,t, J=7.0 Hz), 1.85-2.05 (2H, m), 4.00-4.15 (4H, m), 6.32 (2H, d, J=13.0Hz), 6.80-7.00 (3H, m), 7.08 (1H, dd, J=4.5, 9.0 Hz), 7.61 (2H, t, J=8.9Hz), 7.78 (1H, s).

Example 192

Production of di-tert-butyl8-(cyclohexylmethylamino)-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.02-1.90 (28H, m), 2.50-2.75 (1H, m), 2.78 (3H,s), 3.84 (3H, s), 5.97 (1H, dd, J=9.4, 10.7 Hz), 6.80-7.05 (3H, m), 7.42(1H, dd, J=5.1, 8.8 Hz), 7.51 (1H, dd, J=9.4, 12.1 Hz), 7.64 (2H, d,J=8.8 Hz), 7.71 (1H, s).

Example 193

Production of di-tert-butyl5-fluoro-3-(2-fluoro-4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.11 (3H, t, J=7.5 Hz), 1.36 (18H, s), 1.85-2.05(2H, m), 3.82 (3H, s), 4.07 (2H, t, J=6.6 Hz), 6.30 (2H, d, J=12.6 Hz),6.60-6.80 (2H, m), 6.96 (1H, dd, J=9.0, 10.8 Hz), 7.10 (1H, dd, J=4.5,9.0 Hz), 7.51 (1H, t, J=8.4 Hz), 7.79 (1H, s).

Example 194

Production of di-tert-butyl8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 0.35-0.50 (2H, m), 0.60-0.75 (2H, m), 1.25-1.45(19H, m), 3.83 (3H, s), 3.95 (2H, d, J=7.1 Hz), 6.40 (2H, d, J=13.1 Hz),6.85-7.00 (3H, m), 7.04 (1H, dd, J=4.6, 9.0 Hz), 7.63 (2H, d, J=8.9 Hz),7.79 (1H, s).

Example 195

Production of di-tert-butyl8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.36 (18H, s), 1.55 (3H, t, J=7.0 Hz), 3.83 (3H,s), 4.19 (2H, q, J=7.0 Hz), 6.33 (2H, d, J=12.8 Hz), 6.90-7.00 (3H, m),7.08 (1H, dd, J=4.5, 9.0 Hz), 7.63 (2H, d, J=8.8 Hz), 7.77 (1H, s).

Example 196

Production of di-tert-butyl8-cyclobutylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.36 (18H, s), 1.85-2.10 (4H, m), 2.15-2.30 (2H,m), 2.85-3.00 (1H, m), 3.83 (3H, s), 4.07 (2H, d, J=7.0 Hz), 6.30 (2H,d, J=13.2 Hz), 6.90-7.00 (3H, m), 7.07 (1H, dd, J=4.5, 9.0 Hz), 7.63(2H, d, J=8.9 Hz), 7.79 (1H, s).

Example 197

Production of di-tert-butyl5,6-difluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.12 (3H, t, J=7.4 Hz), 1.36 (18H, s), 1.90-2.05(2H, m), 3.83 (3H, s), 4.06 (2H, t, J=6.6 Hz), 6.28 (2H, d, J=13.2 Hz),6.94 (2H, d, J=8.9 Hz), 7.02 (1H, dd, J=6.8, 11.6 Hz), 7.62 (2H, d,J=8.9 Hz), 7.78 (1H, s).

Example 198

Production of di-tert-butyl5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.11 (3H, t, J=7.5 Hz), 1.37 (18H, s), 1.85-2.00(2H, m), 3.93 (3H, s), 4.06 (2H, t, J=6.6 Hz), 6.34 (2H, d, J=13.1 Hz),6.94 (1H, dd, J=9.0, 11.1 Hz), 7.06 (1H, dd, J=4.5, 9.0 Hz), 7.81 (1H,s), 8.01 (1H, s), 8.38 (1H, s).

Example 199

Production of di-tert-butyl5-fluoro-4-oxo-8-propoxy-3-pyrimidin-5-yl-4H-quinolin-1-ylmethylphosphate

The above compound was prepared in the same manner as in Example 23using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.13 (3H, t, J=7.5 Hz), 1.36 (18H, s), 1.90-2.10(2H, m), 4.10 (2H, t, J=6.6 Hz), 6.36 (2H, d, J=13.8 Hz), 7.01 (1H, dd,J=9.0, 10.9 Hz), 7.16 (1H, dd, J=4.5, 9.0 Hz), 7.96 (1H, s), 9.08 (2H,s), 9.15 (1H, s).

Example 200

Production of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.4 Hz), 1.75-1.90 (2H, m), 3.77(3H, s), 4.07 (2H, t, J=6.5 Hz), 6.26 (2H, d, J=11.2 Hz), 6.96 (2H, d,J=8.9 Hz), 7.06 (1H, dd, J=9.1, 11.6 Hz), 7.33 (1H, dd, J=4.5, 9.1 Hz),7.58 (2H, d, J=8.9 Hz), 8.00 (1H, s).

Example 201

Production of[3-(2,4-dichloro-phenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (3H, t, J=7.4 Hz), 1.80-1.95 (2H, m), 4.10(2H, t, J=6.5 Hz), 6.24 (2H, d, J=11.2 Hz), 7.13 (1H, dd, J=9.0, 11.4Hz), 7.40 (1H, dd, J=4.6, 9.0 Hz), 7.42 (1H, d, J=8.2 Hz), 7.52 (1H, dd,J=2.1, 8.2 Hz), 7.69 (1H, d, J=2.1 Hz), 7.97 (1H, s).

Example 202

Production of[3-(2,4-dimethoxyphenyl)-8-ethoxy-5-fluoro-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.45 (3H, t, J=6.9 Hz), 3.69 (3H, s), 3.80 (3H,s), 4.19 (2H, q, J=6.9 Hz), 6.20 (2H, d, J=9.7 Hz), 6.56 (1H, dd, J=2.4,8.2 Hz), 6.61 (1H, d, J=2.4 Hz), 7.07 (1H, dd, J=9.0, 11.5 Hz), 7.16(1H, d, J=8.2 Hz), 7.35 (1H, dd, J=4.5, 9.0 Hz), 7.80 (1H, s).

Example 203

Production of[3-(4-ethoxyphenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.05 (3H, t, J=7.4 Hz), 1.35 (3H, t, J=7.0 Hz),1.75-1.95 (2H, m), 4.00-4.15 (4H, m), 6.28 (2H, d, J=11.2 Hz), 6.96 (2H,d, J=8.8 Hz), 7.08 (1H, dd, J=9.0, 11.6 Hz), 7.35 (1H, dd, J=4.5, 9.0Hz), 7.59 (2H, d, J=8.8 Hz), 8.03 (1H, s).

Example 204

Production of[5-fluoro-3-(2-fluoro-4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (3H, t, J=7.4 Hz), 1.75-1.95 (2H, m), 3.81(3H, s), 4.09 (2H, d, J=6.9 Hz), 6.24 (2H, d, J=10.9 Hz), 6.75-7.00 (2H,m), 7.11 (1H, dd, J=9.0, 11.4 Hz), 7.24-7.50 (2H, m), 7.95 (1H, s).

Example 205

Production of[8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.35-0.45 (2H, m), 0.55-0.70 (2H, m), 1.30-1.45(1H, m), 3.79 (3H, s), 3.99 (2H, d, J=7.2 Hz), 6.36 (2H, d, J=11.2 Hz),6.98 (2H, d, J=8.9 Hz), 7.07 (1H, dd, J=9.0, 11.6 Hz), 7.33 (1H, dd,J=4.5, 9.0 Hz), 7.60 (2H, d, J=8.9 Hz), 8.03 (1H, s).

Example 206

Production of[8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.45 (3H, t, J=6.9 Hz), 3.79 (3H, s), 4.19 (2H,q, J=6.9 Hz), 6.28 (2H, d, J=10.8 Hz), 6.98 (2H, d, J=8.9 Hz), 7.08 (1H,dd, J=9.0, 11.6 Hz), 7.36 (1H, dd, J=4.5, 9.0 Hz), 7.60 (2H, d, J=8.9Hz), 8.03 (1H, s).

Example 207

Production of[8-cyclobutylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.60-2.20 (6H, m), 2.70-2.95 (1H, m), 3.79 (3H,s), 4.11 (2H, d, J=6.9 Hz), 6.25 (2H, d, J=11.5 Hz), 6.97 (2H, d, J=8.9Hz), 7.08 (1H, dd, J=9.0, 11.5 Hz), 7.35 (1H, dd, J=4.5, 9. Hz), 7.60(2H, d, J=8.9 Hz), 8.02 (1H, s).

Example 208

Production of[5,6-difluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (3H, t, J=7.4 Hz), 1.705-2.00 (2H, m), 3.78(3H, s), 4.12 (2H, t, J=6.5 Hz), 6.25 (2H, d, J=11.5 Hz), 6.98 (2H, d,J=8.8 Hz), 7.50-7.70 (3H, m), 8.07 (1H, s).

Example 209

Production of[8-(cyclohexylmethylamino)-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 0.75-2.00 (10H, m), 3.79 (3H, s), 3.83 (3H, s),3.90-4.60 (1H, m), 5.85 (1H, d, J=9.5 Hz), 6.48 (1H, d, J=9.5 Hz), 7.00(2H, d, J=8.9 Hz), 7.33 (1H, dd, J=8.6, 11.6 Hz), 7.52 (2H, d, J=8.9Hz), 8.16 (1H, dd, J=3.2, 8.6 Hz), 8.22 (1H, s).

Example 210

Production of[5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (3H, t, J=7.4 Hz), 1.75-1.95 (2H, m),3.80-4.15 (5H, m), 6.29 (2H, d, J=10.5 Hz), 7.07 (1H, dd, J=9.0, 11.6Hz), 7.32 (1H, dd, J=4.5, 9.0 Hz), 7.87 (1H, s), 8.31 (1H, s), 8.32 (1H,s).

Example 211

Production of(5-fluoro-4-oxo-8-propoxy-3-pyrimidin-5-yl-4H-quinolin-1-ylmethyl)monophosphate

The above compound was prepared in the same manner as in Example 24using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.05 (3H, t, J=6.6 Hz), 1.75-1.95 (2H, m), 4.11(2H, t, J=6.5 Hz), 6.32 (2H, d, J=12.0 Hz), 7.17 (1H, dd, J=9.1, 11.4Hz), 7.43 (1H, dd, J=4.5, 9.1 Hz), 8.39 (1H, s), 9.10 (2H, s), 9.13 (1H,s).

Example 212

Production of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 204-206° C.

¹H-NMR (D₂O) δ ppm: 0.97 (3H, t, J=7.4 Hz), 1.75-1.85 (2H, m), 3.76 (3H,s), 4.00 (2H, t, J=6.7 Hz), 6.04 (2H, d, J=9.1 Hz), 6.90-7.05 (3H, m),7.18 (1H, dd, J=4.6, 9.1 Hz), 7.42 (2H, d, J=8.7 Hz), 8.14 (1H, s).

Example 213

Production of[3-(2,4-dichlorophenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

Melting point: 208-210° C.

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

¹H-NMR (D₂O) δ ppm: 0.96 (3H, t, J=7.5 Hz), 1.75-1.95 (2H, m), 4.07 (2H,t, J=6.7 Hz), 6.08 (2H, d, J=8.8 Hz), 7.05 (1H, dd, J=9.1, 12.2 Hz),7.30 (1H, dd, J=4.7, 9.1 Hz), 7.32-7.40 (2H, m), 7.50-7.55 (1H, m), 8.21(1H, s).

Example 214

Production of[3-(2,4-dimethoxyphenyl)-8-ethoxy-5-fluoro-4-oxo-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 205-207° C.

¹H-NMR (D₂O) δ ppm: 1.40 (3H, t, J=7.0 Hz), 3.66 (3H, s), 3.77 (3H, s),4.16 (2H, q, J=7.0 Hz), 6.03 (2H, d, J=8.2 Hz), 6.55-6.65 (2H, m), 7.02(1H, dd, J=9.0, 12.3 Hz), 7.17 (1H, d, J=9.0 Hz), 7.28 (1H, dd, J=4.7,9.0 Hz), 8.09 (1H, s).

Example 215

Production of[5-fluoro-3-(4-ethoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 200-202° C.

¹H-NMR (D₂O) δ ppm: 0.93 (3H, t, J=7.5 Hz), 1.27 (3H, t, J=7.0 Hz),1.70-1.90 (2H, m), 3.95-4.10 (4H, m), 6.03 (2H, d, J=8.9 Hz), 6.90-7.05(3H, m), 7.20 (1H, dd, J=4.6, 9.1 Hz), 7.40 (2H, d, J=8.7 Hz), 8.15 (1H,s).

Example 216

Production of[5-fluoro-3-(2-fluoro-4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 208-210° C.

¹H-NMR (D₂O) δ ppm: 0.57 (3H, t, J=7.4 Hz), 1.70-1.85 (2H, m), 3.69 (3H,s), 3.96 (2H, d, J=6.7 Hz), 5.98 (2H, d, J=8.9 Hz), 6.65-6.75 (2H, m),6.95 (1H, dd, J=8.4, 12.2 Hz), 7.15-7.30 (2H, m), 8.12 (1H, s).

Example 217

Production of[8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 202-204° C.

¹H-NMR (D₂O) δ ppm: 0.20-0.35 (2H, m), 0.40-0.60 (2H, m), 1.20-1.45 (1H,m), 3.73 (3H, s), 3.90 (2H, d, J=7.3 Hz), 6.09 (2H, d, J=9.2 Hz),6.80-7.05 (3H, m), 7.21 (1H, dd, J=4.7, 9.0 Hz), 7.40 (2H, d, J=8.8 Hz),8.15 (1H, s).

Example 218

Production of[8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 206-208° C.

¹H-NMR (D₂O) δ ppm: 1.38 (3H, t, J=7.0 Hz), 3.73 (3H, s), 4.10 (2H, q,J=7.0 Hz), 6.01 (2H, d, J=8.4 Hz), 6.90-7.05 (3H, m), 7.19 (1H, dd,J=4.6, 8.9 Hz), 7.40 (2H, d, J=8.8 Hz), 8.13 (1H, s).

Example 219

Production of[8-cyclobutylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 205-207° C.

¹H-NMR (D₂O) δ ppm: 1.63-2.10 (6H, m), 2.75-3.00 (1H, m), 3.72 (3H, s),4.00 (2H, d, J=7.2 Hz), 5.99 (2H, d, J=9.8 Hz), 6.90-7.05 (3H, m), 7.17(1H, dd, J=4.7, 9.1 Hz), 7.40 (2H, d, J=8.7 Hz), 8.14 (1H, s).

Example 220

Production of[5,6-difluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 205-206° C.

¹H-NMR (D₂O) δ ppm: 0.94 (3H, d, J=7.5 Hz), 1.70-1.95 (2H, m), 3.73 (3H,s), 4.01 (2H, t, J=6.5 Hz), 6.02 (2H, d, J=9.1 Hz), 6.90-7.50 (5H, m),8.16 (1H, s).

Example 221

Production of[8-(cyclohexylmethylamino)-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 196-198° C.

¹H-NMR (D₂O) δ ppm: 0.60-1.75 (10H, m), 2.40-2.60 (1H, m), 2.66 (3H, s),3.73 (3H, s), 5.80 (1H, dd, J=7.7, 7.8 Hz), 6.80-7.05 (4H, m), 7.35-7.55(3H, m), 8.18 (1H, s).

Example 222

Production of[5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 212-214° C.

¹H-NMR (D₂O) δ ppm: 0.94 (3H, d, J=7.5 Hz), 1.70-1.90 (2H, m), 3.79 (3H,s), 3.93 (2H, t, J=6.7 Hz), 5.99 (2H, d, J=9.1 Hz), 6.92 (1H, dd, J=9.0,12.3 Hz), 7.08 (1H, dd, J=4.7, 9.0 Hz), 7.86 (1H, s), 8.02 (1H, s), 8.30(1H, s).

Example 223

Production of(5-fluoro-4-oxo-8-propoxy-3-pyrimidin-5-yl-4H-quinolin-1-ylmethyl)monophosphatedisodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 205-207° C.

¹H-NMR (D₂O) δ ppm: 0.96 (3H, d, J=7.4 Hz), 1.70-1.95 (2H, m), 4.06 (2H,t, J=6.7 Hz), 6.10 (2H, d, J=9.6 Hz), 7.05 (1H, dd, J=8.9, 12.1 Hz),7.29 (1H, dd, J=4.4, 8.9 Hz), 8.41 (1H, s), 8.94 (2H, s), 8.96 (1H, s).

Example 224

Production of ethyl4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-pyrrolidin-1-yl-4H-quinolin-1-yl]butyrate

The above compound was prepared in the same manner as in Example 31using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.23-1.29 (3H, t, J=7.1 Hz), 1.70-1.78 (2H, m),1.91-2.15 (6H, m), 2.52-2.87 (2H, m), 3.14-3.44 (2H, m), 4.00-4.08 (2H,q, J=6.1 Hz), 4.59-4.64 (2H, t, J=6.9 Hz), 6.87-7.03 (3H, m), 7.14-7.37(1H, m), 7.51 (1H, s), 7.55-7.73 (2H, m).

Example 225

Production of4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-pyrrolidin-1-yl-4H-quinolin-1-yl]butyricacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.63-1.81 (2H, m), 1.87-2.14 (6H, m), 2.57-2.81(2H, m), 3.14-3.39 (2H, m), 3.81 (3H, s), 4.61-4.66 (2H, t, J=6.8 Hz),6.84-7.01 (3H, m), 7.25-7.30 (1H, m), 7.52-7.63 (3H, m).

Example 226

Production ofN-butyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-pyrrolidin-1-yl-4H-quinolin-1-yl]butylamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Brown Amorphous

¹H-NMR (CDCl₃) δ ppm: 0.82-0.88 (3H, t, J=7.1 Hz), 1.21-1.31 (4H, m),1.74-1.77 (2H, m), 1.89-2.10 (2H, m), 2.60-2.80 (2H, m), 3.04-3.12 (2H,m), 3.20-3.45 (2H, m), 3.82 (3H, s), 4.58-4.63 (2H, m), 5.20-5.30 (1H,m), 6.88-6.94 (2H, m), 7.23-7.28 (1H, m), 7.52 (1H, s), 7.61-7.67 (2H,m).

Example 227

Production of4-[4-(5-fluoro-4-oxo-8-pyrrolidin-1-yl-1,4-dihydroquinolin-3-yl)phenoxy]butyricacid

The above compound was prepared in the same manner as in Example 32using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.80-2.00 (6H, m), 2.33-2.39 (2H, t, J=7.2 Hz),3.00-3.05 (4H, m), 3.96-4.01 (2H, t, J=6.4 Hz), 6.84-6.93 (3H, m),7.32-7.37 (1H, m), 7.50-7.53 (2H, d, J=8.7 Hz), 7.79 (1H, s), 10.95 (1H,s), 11.80-12.20 (1H, brs).

Example 228

Production ofN-butyl-4-[4-(5-fluoro-4-oxo-8-pyrrolidin-1-yl-1,4-dihydroquinolin-3-yl)phenoxy]butylamide

The above compound was prepared in the same manner as in Example 33using appropriate starting materials.

Pale Yellow Powder

¹H-NMR (DMSO-d₆) δ ppm: 0.81-0.87 (3H, t, J=7.0 Hz), 1.19-1.40 (4H, m),1.85-1.95 (6H, m), 2.19-2.25 (2H, t, J=7.2 Hz), 2.97-3.10 (6H, m),3.93-3.98 (2H, t, J=6.3 Hz), 6.85-6.93 (3H, m), 7.34-7.39 (1H, m),7.51-7.54 (2H, d, J=8.3 Hz), 7.75-7.83 (2H, m), 10.97 (1H, brs).

Example 229

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl(tert-butoxycarbonylmethylamino)acetate

Sodium iodide (1.4 g, 0.9 mmol) and sodium hydride (60% oil base, 220mg, 5.5 mmol) were added to a DMF solution (15 ml) of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (1.0 g, 3.0mmol) and stirred at room temperature for 10 minutes.Chloromethyl(tert-butoxycarbonylmethylamino)acetate (2.52 g, 10.6 mmol)was added to the reaction mixture while ice-cooling, and then themixture was stirred at room temperature for 3 hours. An aqueous sodiumbicarbonate solution was added to the reaction mixture and then themixture was subjected to extraction using ethyl acetate. Thethus-obtained organic layer was dried over sodium sulfate, and thenconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography (n-hexane:ethyl acetate=2:1). Thepurified material was concentrated to dryness under reduced pressure,giving a pale yellow amorphous solid of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl(tert-butoxycarbonylmethylamino)acetate (290 mg, yield: 18%).

¹H-NMR (CDCl₃) δ ppm: 100-1.15 (3H, m), 1.29-1.44 (9H, s), 1.85-2.00(2H, m), 2.88-2.90 (3H, s), 3.84 (3H, s), 3.90-4.15 (4H, m), 6.46-6.51(2H, s), 6.90-7.15 (4H, m), 7.59 (2H, d, J=8.6 Hz), 7.74-7.79 (1H, s).

Example 230

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylmethylaminoacetate hydrochloride

A 4N hydrogen chloride ethylacetate solution (1 ml) was added to anethyl acetate solution (2 ml) of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl(tert-butoxycarbonylmethylamino)acetate(100 mg, 0.19 mmol) and stirred at room temperature for 3 hours. Thedeposited insoluble matter was collected by filtration, washed withacetone, and then dried, giving a white powder of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylmethylaminoacetate hydrochloride (78.3 mg, yield: 88%).

¹H-NMR (DMSO-d₆) δ ppm: 1.03 (3H, t, J=7.4 Hz), 1.80-1.90 (2H, m),2.45-2.60 (3H, m), 3.79 (3H, s), 4.07 (2H, s), 4.10 (2H, t, J=6.6 Hz),6.61 (2H, s), 6.99 (2H, d, J=8.9 Hz), 7.11 (1H, dd, J=9.1, 11.5 Hz),7.39 (1H, dd, J=4.5, 9.1 Hz), 7.60 (2H, d, J=8.9 Hz), 8.17 (1H, s), 9.14(2H, br).

Example 231

Production of5-fluoro-1-(2-morpholin-4-ylethyl)-8-propoxy-3-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 106using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.4 Hz), 1.77-1.88 (6H, m),2.31-2.34 (4H, m), 2.58 (2H, t, J=5.4 Hz), 3.37-3.44 (8H, m), 4.04 (2H,t, J=6.5 Hz), 4.67 (2H, d, J=5.4 Hz), 7.01 (1H, dd, J=9.0 Hz, 11.6 Hz),7.27 (1H, dd, J=4.5 Hz, 9.0 Hz), 7.52 (2H, d, J=8.3 Hz), 7.72 (2H, d,J=8.3 Hz), 8.05 (1H, s).

Example 232

Production of1-chloromethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

A 4N hydrogen chloride ethylacetate solution (2 ml) was added to anethyl acetate solution (3 ml) of di-tert-butyl5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphate (300 mg, 0.55 mmol) while ice-cooling and the mixture wasstirred at room temperature for 2 hours. The deposited insoluble matterwas collected by filtration and dried, giving a white powder of1-chloromethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(18 mg, yield: 92%).

¹H-NMR (CDCl₃) δ ppm: 1.13 (3H, t, J=7.5 Hz), 1.70-2.10 (2H, m), 3.84(3H, s), 4.11 (2H, t, J=6.6 Hz), 6.40 (2H, s), 6.90-7.05 (3H, m), 7.12(1H, dd, J=4.5, 9.0 Hz), 7.51 (1H, s), 8.59 (2H, d, J=8.8 Hz).

Example 233

Production of1-(2-benzyloxyacetyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Benzyloxyacetyl chloride (1.9 ml, 3 equivalent weight) was added to adichloromethane solution (50 ml) of4-(tert-butyldimethylsilyloxy)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-quinolin(1.5 g, 3.4 mmol) while ice-cooling and the mixture was stirredovernight at room temperature. An aqueous sodium bicarbonate solutionwas added to the reaction mixture, followed by extraction using ethylacetate. The thus-obtained organic layer was dried over sodium sulfate,and then concentrated under reduced pressure. The residue was purifiedusing silica gel column chromatography (n-hexane:ethyl acetate=2:1). Thepurified product was concentrated under reduced pressure, giving acolorless oily substance of1-(2-benzyloxyacetyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(250 mg, yield: 15%).

¹H-NMR (CDCl₃) δ ppm: 1.00 (3H, t, J=7.4 Hz), 1.70-1.90 (2H, m), 3.84(3H, s), 3.95 (2H, t, J=6.4 Hz), 4.38 (2H, s), 4.52 (2H, s), 6.94 (2H,d, J=8.8 Hz), 6.95-7.40 (7H, m), 7.57 (2H, d, J=8.8 Hz), 7.92 (1H, s).

Example 234

Production of1-acetyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 233using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.05 (3H, t, J=7.5 Hz), 1.80-2.00 (2H, m), 2.41(3H, s), 3.83 (3H, s), 4.02 (2H, t, J=5.7 Hz), 6.95 (2H, d, J=8.9 Hz),7.00-7.15 (2H, m), 7.59 (2H, d, J=8.9 Hz), 8.02 (1H, s).

Example 235

Production of1-(2-bromoacetyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 233using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 0.95-1.15 (3H, m), 1.70-2.05 (2H, m), 3.80-4.20(7H, m), 6.50-8.00 (7H, m).

Example 236

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-benzyloxybenzoate

The above compound was prepared in the same manner as in Example 229using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.06 (3H, t, J=7.4 Hz), 1.80-2.00 (2H, m), 3.84(3H, s), 4.08 (2H, t, J=6.7 Hz), 5.11 (2H, s), 6.62 (2H, s), 6.90-7.15(6H, m), 7.30-7.45 (5H, m), 7.62 (2H, d, J=8.9 Hz), 7.84 (1H, s), 7.94(2H, d, J=8.9 Hz).

Example 237

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-hydroxybenzoate

10% palladium/carbon (260 mg) was added to a THF (30 ml) and ethanol (15ml) solution of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-benzyloxybenzoate (2.6 g, 4.6 mmol). The mixture was subjected tohydrogen substitution and stirred at room temperature for 3 hours. Aftercompletion of the reaction, the catalyst was removed by conductingfiltration using Celite, and the mixture was concentrated to drynessunder reduced pressure, giving a pale yellow powder of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-hydroxybenzoate (2.22 g, yield: quantitative).

¹H-NMR (CDCl₃) δ ppm: 1.06 (3H, t, J=7.4 Hz), 1.80-2.00 (2H, m), 3.81(3H, s), 4.08 (2H, t, J=6.7 Hz), 6.63 (2H, s), 6.42 (2H, d, J=8.8 Hz),6.90-7.00 (3H, m), 7.10 (1H, dd, J=4.4, 9.0 Hz), 7.22 (1H, br), 7.58(2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz), 7.88 (1H, s).

Example 238

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-(di-tert-butylphosphonooxy)benzoate

5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-hydroxybenzoate (2.2 g, 4.6 mmol) was suspended in acetone (50 ml).Tetrasol (420 mg) and di-tert-butyl diisopropyl phosphoramidite (1.9 ml)were added thereto and the resulting suspension was stirred at roomtemperature for 2 hours. The reaction mixture was ice-cooled, and anaqueous 30% hydrogen peroxide solution (2.9 ml) was added thereto,followed by stirring at the same temperature for 2 hours. An aqueoussodium thiosulphate solution and an aqueous sodium bicarbonate solutionwere added to the reaction mixture. The resulting mixture was stirredand then concentrated under reduced pressure. Water was added to theresidue, followed by extraction using ethyl acetate. The thus-obtainedorganic layer was washed with an aqueous saturated sodium chloridesolution, dried over sodium sulfate, and then concentrated under reducedpressure. The residue was purified using silica gel columnchromatography (n-hexane:ethyl acetate=100:1→2:1). The purified materialwas concentrated to dryness under reduced pressure, giving a whiteamorphous solid of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-(di-tert-butylphosphonooxy)benzoate (2.51 g, yield: 81%).

¹H-NMR (CDCl₃) δ ppm: 1.06 (3H, t, J=7.4 Hz), 1.50 (18H, s), 1.80-2.00(2H, m), 3.84 (3H, s), 4.08 (2H, t, J=6.7 Hz), 6.63 (2H, s), 6.90-7.00(3H, m), 7.10 (1H, dd, J=4.4, 9.0 Hz), 7.26 (2H, d, J=8.5 Hz), 7.62 (2H,d, J=8.7 Hz), 7.83 (1H, s), 7.97 (2H, d, J=8.5 Hz).

Example 239

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-phosphonoxybenzoate

Trifluoro-acetic acid (2 ml) was added to a dichloromethane solution (10ml) of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-(di-tert-butylphosphonooxy)benzoate (500 mg) while ice-cooling, andthen the mixture was stirred at the same temperature for 1 hour. Theresulting mixture was concentrated under reduced pressure at a bathtemperature of not higher than 30° C. The residue was recrystallizedfrom ethyl acetate-n-hexane, giving a pale yellow powder of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-phosphonoxybenzoate (406.7 mg, yield: 98%).

¹H-NMR (DMSO-d₆) δ ppm: 0.93 (3H, t, J=7.4 Hz), 1.60-1.85 (2H, m), 3.79(3H, s), 4.06 (2H, t, J=6.5 Hz), 6.64 (2H, s), 6.98 (2H, d, J=8.8 Hz),7.09 (1H, dd, J=9.1, 11.5 Hz), 7.27 (2H, d, J=8.7 Hz), 7.37 (1H, dd,J=4.4, 9.1 Hz), 7.62 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=8.7 Hz), 8.38(1H, s).

Example 240

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-phosphonoxybenzoate disodium salt

5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-phosphonoxybenzoate (397 mg) was suspended in isopropyl alcohol (10ml) while ice-cooling. A 1N aqueous sodium hydroxide solution (1.5 ml)was added thereto and the suspension was stirred at the same temperaturefor 1 hour. The deposited insoluble matter was collected by filtrationand recrystallized from acetone-water, giving a white powder of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl4-phosphonoxybenzoate disodium salt (338.6 mg).

Melting point: 205-207° C.

¹H-NMR (D₂O) δ ppm: 0.81 (3H, t, J=7.4 Hz), 1.50-2.00 (2H, m), 3.60 (3H,s), 3.89 (2H, t, J=6.7 Hz), 6.30 (2H, s), 6.68 (2H, d, J=8.7 Hz), 6.92(1H, dd, J=9.1, 12.1 Hz), 7.05-7.20 (5H, m), 7.75 (2H, d, J=8.9 Hz),7.79 (1H, s).

Example 241

Production of1-benzyloxymethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 229using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.06 (3H, t, J=7.5 Hz), 1.75-2.00 (2H, m), 3.84(3H, s), 4.00 (2H, t, J=6.6 Hz), 4.44 (2H, s), 5.92 (2H, s), 6.90-7.40(9H, m), 7.59 (2H, d, J=8.8 Hz), 7.76 (1H, s).

Example 242

Production of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyltetrahydro-pyran-2-yl)-1H-quinolin-4-one

1-Bromo-2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl (17.0 g, 41.3 mmol),benzyltri-n-butylammonium bromide (1.3 g, 4.16 mmol), potassiumcarbonate (14.37 g, 104 mmol) and water (0.45 ml) were sequentiallyadded in this order to a chloroform solution (90 ml) of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (6.75 g, 20.6mmol). Chloroform (27 ml) was added to the resulting reaction mixtureand the mixture was then stirred at room temperature for 39 hours. 2Nhydrochloric acid (80 ml) was added to the thus-obtained mixture whileice-cooling, followed by extraction with dichloromethan. Thethus-obtained organic layer was washed with an aqueous saturated sodiumchloride solution and then concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography(dichloromethane:ethyl acetate=30:1→4:1). The purified product wasconcentrated under reduced pressure. The residue was dissolved inethanol (100 ml), and an aqueous solution (8.16 ml) of potassiumhydroxide (5.44 g) was added thereto, followed by stirring at roomtemperature for 3 hours. The resulting reaction mixture was concentratedunder reduced pressure. 2N hydrochloric acid (20.4 ml) was added to theresidue, and extraction was conducted using ethyl acetate. Thethus-obtained organic layer was washed with an aqueous saturated sodiumchloride solution and then concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography(dichloromethane:methanol=50:1→20:1→ethyl acetate:methanol=30:1). Thepurified product was concentrated under reduced pressure, and theresidue was then recrystallized from ethyl acetate, giving a whitepowder of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-yl)-1H-quinolin-4-one(0.38 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.03 (3H, t, J=7.3 Hz), 1.79-1.88 (2H, m),3.24-3.41 (3H, m), 3.54-3.70 (3H, m), 3.76 (3H, s), 3.96-4.11 (2H, m),4.69 (1H, t, J=5.5 Hz), 5.14-5.16 (2H, m), 5.33 (1H, d, J=5.4 Hz), 6.51(1H, d, J=8.9 Hz), 6.94-7.05 (3H, m), 7.29 (1H, dd, J=4.5 Hz, 9.1 Hz),7.54 (2H, d, J=8.8 Hz), 7.99 (1H, s).

Example 243

Production of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-yl)-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 242using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.03 (3H, t, J=7.3 Hz), 1.81-1.89 (2H, m),3.30-3.40 (1H, m), 3.57-3.58 (3H, m), 3.71-3.75 (2H, m), 3.77 (3H, s),3.96-4.12 (2H, m), 4.67-4.76 (2H, m), 4.91 (1H, d, J=5.7 Hz), 5.17 (1H,d, J=5.4 Hz), 6.43 (1H, d, J=8.8 Hz), 6.96-7.05 (3H, m), 7.28 (1H, dd,J=4.5 Hz, 9.1 Hz), 7.52 (2H, d, J=8.8 Hz), 8.05 (1H, s).

Example 244

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl(di-tert-butylphosphonooxy)acetate

The above compound was prepared in the same manner as in Example 23using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.09 (3H, t, J=7.4 Hz), 1.44 (18H, s), 1.80-2.00(2H, m), 3.84 (3H, s), 4.06 (2H, t, J=6.7 Hz), 4.53 (2H, d, J=8.9 Hz),6.51 (2H, s), 6.90-7.00 (3H, m), 7.08 (1H, dd, J=4.5, 9.0 Hz), 7.59 (2H,d, J=8.9 Hz), 7.73 (1H, s).

Example 245

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphonoxyacetate

The above compound was prepared in the same manner as in Example 239using appropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, d, J=7.4 Hz), 1.65-1.90 (2H, m), 3.79(3H, s), 4.07 (2H, t, J=6.6 Hz), 4.45 (2H, d, J=9.0 Hz), 6.49 (2H, s),6.98 (2H, d, J=8.9 Hz), 7.09 (1H, dd, J=9.1, 11.5 Hz), 7.36 (1H, dd,J=4.4, 9.1 Hz), 7.59 (2H, d, J=8.9 Hz), 8.16 (1H, s).

Example 246

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethylphosphonoxyacetate disodium salt

The above compound was prepared in the same manner as in Example 25using appropriate starting material.

Melting point: 160-162° C.

¹H-NMR (D₂O) δ ppm: 0.84 (3H, d, J=7.4 Hz), 1.55-1.70 (2H, m), 3.61 (3H,s), 3.86 (2H, t, J=6.6 Hz), 4.25 (2H, d, J=6.9 Hz), 6.26 (2H, s), 6.73(2H, d, J=8.7 Hz), 6.88 (1H, dd, J=9.2, 12.1 Hz), 7.08 (1H, dd, J=4.5,9.2 Hz), 7.18 (2H, d, J=8.7 Hz), 7.78 (1H, s).

Example 247

Production of5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl(S)-2,6-bis-tert-butoxycarbonylaminohexanate

The above compound was prepared in the same manner as in Example 229using appropriate starting material.

¹H-NMR (CDCl₃) δ ppm: 1.10 (3H, t, J=7.4 Hz), 1.20-1.75 (24H, m),1.80-2.00 (2H, m), 2.85-3.10 (2H, m), 3.84 (3H, s), 4.07 (2H, t, J=6.6Hz), 4.15-4.30 (1H, m), 4.45-4.65 (1H, m), 5.00-5.25 (1H, m), 6.48 (2H,s), 6.90-7.05 (3H, m), 7.10 (1H, dd, J=4.5, 9.0 Hz), 7.59 (2H, d, J=8.8Hz), 7.74 (1H, s).

Example 248

Production of1-(1-ethylsulfanylethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 229using appropriate starting materials.

¹H-NMR (CDCl₃) δ ppm: 1.08 (3H, t, J=7.3 Hz), 1.12 (3H, t, J=7.3 Hz),1.79 (3H, d, J=6.7 Hz), 1.90-2.00 (2H, m), 2.30 (1H, q, J=7.3 Hz), 2.33(1H, q, J=7.3 Hz), 3.85 (3H, s), 4.00 (1H, td, J=6.7, 8.9 Hz), 4.12 (1H,td, J=6.7, 8.9 Hz), 6.80-7.10 (5H, m), 7.66 (2H, d, J=8.8 Hz), 8.29 (1H,s).

Example 249

Production of 5-fluoro-7-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 1 usingappropriate starting material.

¹H-NMR (DMSO-d₆) δ ppm: 3.76 (3H, s), 3.83 (3H, s), 6.65 (1H, d, J=13.6Hz), 6.76 (1H, s), 6.92 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.90(1H, d, J=5.8 Hz), 11.75 (1H, brs).

Example 250

Production of1-ethyl-5-fluoro-7-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one

The above compound was prepared in the same manner as in Example 3 usingappropriate starting materials.

¹H-NMR (DMSO-d₆) δ ppm: 1.33 (3H, t, J=6.9 Hz), 3.75 (3H, s), 3.89 (3H,s), 4.27 (2H, q, J=7.0 Hz), 6.74 (1H, d, J=13.7 Hz), 6.82 (1H, s), 6.92(2H, d, J=8.7 Hz), 7.55 (2H, d, J=8.7 Hz), 8.04 (1H, s).

Example 251

Production of ethyl4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinolin-2-yl]butyrate

The above compound was prepared in the same manner as in Example 2 usingappropriate starting materials.

White Powder (Ethyl Acetate)

Melting point: 177-179° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.00 (3H, t, J=7.4 Hz), 1.06 (3H, t, J=7.1 Hz),1.67-1.88 (4H, m), 2.16 (2H, t, J=7.4 Hz), 2.58 (2H, t, J=7.0 Hz), 3.76(3H, s), 3.90 (2H, q, J=7.1 Hz), 4.14 (2H, t, J=6.6 Hz), 6.81-6.94 (3H,m), 7.06 (2H, d, J=8.6 Hz), 7.15 (1H, dd, J=4.0 Hz, 8.8 Hz), 10.40 (1H,brs).

Example 252

Production of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedipotassium salt

[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate(800 mg, 1.83 mmol) was suspended in isopropyl alcohol (30 ml). A1N-potassium hydroxide aqueous solution (3.66 ml, 3.66 mmol) was addedthereto at 0° C. The resulting mixture was stirred at 0° C. for 1.5hours. The generated insoluble matter was collected by filtration,recrystallized from acetone-water and then dried, giving a white powderof[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedipotassium salt (445 mg, yield: 47%).

Melting point: 184-186° C.

¹H-NMR (D₂O) δ ppm: 0.97 (3H, t, J=7.4 Hz), 1.79-1.88 (2H, m), 3.76 (3H,s), 4.01 (2H, t, J=6.7 Hz), 6.05 (2H, d, J=9.1 Hz), 6.93-7.01 (3H, m),7.19 (1H, dd, J=4.6, 9.1 Hz), 7.43 (2H, d, J=8.8 Hz), 8.16 (1H, s).

Example 253

Production of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatecalcium salt

[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt (800 mg, 1.66 mmol) was dissolved in water (4 ml). Acalcium chloride (202 mg, 1.82 mmol) aqueous solution (1 ml) was addedthereto at room temperature. The deposited solid was collected byfiltration, washed with water and acetone, and then dried, giving awhite powder of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatecalcium salt (690 mg, yield: 87%).

Melting point: 255-258° C. (Decomposed)

¹H-NMR (DMSO-d₆, 80° C.) δ ppm: 0.79-0.89 (3H, m), 1.68-1.76 (2H, m),3.62 (3H, s), 3.91-4.01 (2H, m), 6.09-6.16 (2H, m), 6.74-6.90 (3H, m),7.09-7.15 (1H, m), 7.40-7.70 (2H, m), 8.32 (1H, s).

Example 254

Production of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatemagnesium salt

[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatedisodium salt (1.0 g, 2.07 mmol) was suspended in methanol (10 ml). Amethanol solution (4.3 ml) of magnesium chloride (198 mg, 2.08 mmol) wasadded thereto at room temperature. The resulting mixture was stirred atroom temperature for 20 minutes. The solid deposited after condensationwas collected by filtration, washed with water and acetone, and thendried, giving a white powder of[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphatemagnesium salt (845 mg, yield: 88%).

Melting point: 265-269° C. (Decomposed)

¹H-NMR (DMSO-d₆, 80° C.) δ ppm: 0.99 (3H, t, J=7.4 Hz), 1.76-1.86 (2H,m), 3.64 (3H, s), 4.05 (2H, t, J=6.5 Hz), 6.09 (2H, d, J=10.4 Hz),6.80-6.98 (3H, m), 7.24 (1H, dd, J=4.6, 8.6 Hz), 7.58 (2H, d, J=8.7 Hz),8.00 (1H, s).

Pharmacological Test Example 1 Evaluation of the Improvement ofMitochondrial Dysfunction Using Human Neuroblastoma Cell Lines SH-SY5YTreated with 1-methyl-4-phenylpyridinium (MPP⁺)

In human neuroblastoma cell lines SH-SY5Y in which mitochondrialactivity was injured by MPP⁺ treatment (Bollimuntha S. et al., J BiolChem, 280, 2132-2140 (2005) and Shang T. et al., J Biol Chem, 280,34644-34653 (2005)), the improvement of mitochondrial dysfunction wasevaluated on the basis of measurement values for mitochondrial oxidationreduction activity using Alamar Blue fluorescent dye after the compoundaddition (Nakai M. et al, Exp Neurol, 179, 103-110 (2003)).

The human neuroblastoma cell lines SH-SY5Y were cultured in Dulbecco'sModified Eagle's Medium containing 10% fetal bovine serum (DMEMcontaining 50 units/ml penicillin and 50 μg/ml streptomycin asantibiotics) at 37° C. in the presence of 5% carbon dioxide. Cells werescattered on a poly-D-lysine-coated 96-well black plate at aconcentration of 3-6×10⁴ cells/cm² (medium amount: 100 μl/well), andcultured in the above medium for two days. Further, the medium waschanged to DMEM containing a 1% N2 supplement (N2-DMEM) or to a medium(100 μl/well) in which 1.5 mM MPP⁺ was dissolved. The cells werecultured therein for 39 to 48 hours, and then subjected to amitochondrial oxidation reduction activity measurement system. A samplecompound that had been previously dissolved in dimethyl sulfoxide (DMSO)was diluted with N2-DMEM, and added in a volume of 10 μl/well 24 hoursbefore the activity measurement (final compound concentration: 0.01 to 1μg/ml).

After removal of the medium by suction, a balanced salt solutioncontaining 10% Alamar Blue (154 mM sodium chloride, 5.6 mM potassiumchloride, 2.3 mM calcium chloride, 1.0 mM magnesium chloride, 3.6 mMsodium bicarbonate, 5 mM glucose, 5 mM HEPES, pH 7.2) was added in avolume of 100 μl/well, and reacted in an incubator at 37° C. for 1 hour.The fluorescent intensity was detected using a fluorescence detector (aproduct of Hamamatsu Photonics K.K., excitation wavelength 530 nm,measurement wavelength 580 nm) to thereby measure the mitochondrialoxidation reduction activity.

The fluorescent intensity of the well of the cells cultured in a mediumcontaining MPP⁺ and in each of the sample compounds was relativelyevaluated based on the 100% fluorescent intensity of the well of thecells cultured in a medium containing DMSO alone (final concentration:0.1%). When the MPP⁺-induced cell groups exhibited higher florescentintensity than the cell groups cultured in DMSO alone, the test compoundwas judged to have improved the activity of the mitochondrialdysfunction.

TABLE 1 Evaluation of the improvement of mitochondrial dysfunction usinghuman neuroblastoma cell lines SH-SY5Y treated with1-methyl-4-phenylpyridinium (MPP⁺) Test Compound Fluorescence Intensity(%) Concentration 0 0.01 0.03 0.1 0.3 1 (μg/ml) Compound of 51 66 71 7880 75 Example 7 Compound of 48 80 74 83 82 68 Example 12 Compound of 4669 67 86 90 89 Example 36 Compound of 46 60 81 92 93 80 Example 48Compound of 59 64 65 68 74 65 Example 57 Compound of 48 78 64 68 67 65Example 69 Compound of 45 53 58 57 60 55 Example 139 Compound of 41 5955 67 71 66 Example 161 Compound of 43 61 61 63 60 63 Example 163Compound of 49 61 61 65 67 68 Example 171 Compound of 36 46 62 63 70 72Example 212 Compound of 46 59 64 66 62 73 Example 222

Pharmacological Test 2 Evaluation of Dopaminergic Neuronal ProtectiveActivity Using C57BL/6 Mouse Treated with 1-methyl-4-phenyl1,2,3,6-tetrahydro Pyridine (MPTP)

Using a mouse having MPTP-induced dopaminergic neurons (Chan P. et al.,J Neurochem, 57, 348-351 (1991)), the dopamine neuroprotective activitywas evaluated based on dopamine contents and protein levels of tyrosinehydroxylase (TH) and dopamine transporter (DAT) (i.e., dopaminergicneuronal marker proteins) in the brain corpus striatum region after thecompound administration (Mori A. et al., Neurosci Res, 51, 265-274(2005)). A male C57BL/6 mouse (provided by Japan Charles River Inc., 10to 12 weeks) was used as a test animal. MPTP was dissolved in aphysiological salt solution so that the concentration became 4 mg/ml,and then administered to the mouse subcutaneously in a volume of 10ml/kg. The test compound was suspended in a 5% gum arabic/physiologicalsalt solution (w/v) so that a compound having a concentration of 1 mg/mlcould be obtained. Each of the test compounds or solvents thereof wasorally administered to the mouse after 30 minutes, 24 hours, and 48hours of the MPTP administration. The mouse was decapitated after 72hours of the MPTP administration, the brain was removed, and each sideof the striatum was dissected.

The left striatum was used as a sample to detect the protein levels byWestern blot analysis. Each tissue was homogenized in a HEPES buffersucrose solution (0.32 M sucrose, 4 μg/ml pepstatin, 5 μg/ml aprotinin,20 μg/ml trypsin inhibitor, 4 μg/ml leupeptin, 0.2 mMphenylmethanesulfonyl fluoride, 2 mM ethylenediaminetetraacetic acid(EDTA), 2 mM ethylene glycol bis(β aminoethyl ether) tetraacetic acid,20 mM HEPES, pH 7.2), and assayed for protein using a bicinchoninic acidkit for protein assay (provided by Pierce Corporation). Each homogenizedsample, having an equal amount of protein that had been dissolved in aLaemmli sample buffer solution, was subjected to electrophoresis throughsodium dodecyl sulfurate polyacrylamide gels. The protein separated byelectrophoresis was electrically transferred to polyvinylidene fluoridemembranes. The membranes were reacted with specific primary antibodiesfor TH, DAT, and housekeeping proteins, i.e., the αl subunit ofNa⁺/K⁺-ATPase and actin (Na⁺/K⁺-ATPase, a product of UpStateBiotechnology Inc.; others are products of Chemi-Con Corporation).Subsequently, a horseradish peroxidase-labeled secondary antibody (aproduct of Amersham K.K.) for each primary antibody was fixed, and thechemiluminescence associated with enzyme activity of peroxidase wasdetected using X-ray film. The density of the protein band on the filmwas analyzed using a densitometer (a product of Bio-rad LaboratoriesInc.) to obtain the TH value relative to Na⁺/K⁺-ATPase and the DAT valuerelative to actin.

The right striatum, the tissue weight of which was measured immediatelyafter dissection, was used as an analysis sample for determining thedopamine content. Each tissue was homogenized in a 0.1 N perchloric acidsolution containing isoproterenol as an internal standard substance ofthe measurement, using an ultrasonic homogenizer while being cooled withice. The supernatant obtained from 20,000 g of homogenate that had beencentrifuged at 4° C. for 15 minutes was subjected to a high performanceliquid chromatography with a reversed phase column (a product of EicomCorporation). A mobile phase 15% methanol 0.1 M citric acid/0.1 M sodiumacetate buffer solution (containing 190 mg/L 1-sodium octane sulfonate,5 mg/L EDTA, pH 3.5) was flowed at a rate of 0.5 ml/min, and thedopamine peak of each sample was detected using an electrochemicaldetector (applied voltage+750 mV vs. Ag/AgCl, a product of EicomCorporation). With reference to the identified dopamine peak, thedopamine content per tissue weight was calculated in each sample usinganalysis software (a product of Gilson Inc.). In both analyses, thevalue of the sample derived from the MPTP-induced mice in which only thetest compound or the solvent was administered was expressed relative tothe value of the sample derived from the mice without MPTP treatment(100%). Values were analyzed statistically using a nonclinicalstatistical analysis system. Values of significance probability<0.05were defined as statistically significant. In the MPTP-induced mice,when the test drug group showed an increase in protein level compared tothe solvent group, and a significant difference was observed betweenthese groups in the t-assay, the test drug was judged to have dopamineneuroprotective activity.

Pharmacological Test Example 3 Evaluation of the Neuroprotective Actionin Rat Middle Cerebral Artery Occlusion-Reperfusion Model

The neuroprotective action of an experimental compound was evaluated ina middle cerebral artery (MCA) occlusion-reperfusion rat model of stroke[Koizumi J. et al., Jpn J Stroke, 8, 1-8 (1986)] using the cerebralinfarct volume as an index [Kitagawa H. et al., Neurol Res, 24, 317-323(2002)].

Male Wistar rats (12-16 weeks old, Japan SLC, Inc.) were used as theexperimental animals. Each rat was kept at 37° C. under isofluraneanesthetization, and immobilized in the supine position while breathingvoluntarily. Each rat was subjected to a median incision in the cervicalregion, and the right common carotid artery (CCA), the right externalcarotid artery (ECA) and the right internal carotid artery (ICA) wereexposed without damaging the vagus nerve. Subsequently, the right CCAand the right ECA were ligated, the right ICA was controlled with asuture at its origin and a small incision was made in the right CCA. Theocclusion of the right MCA at its origin was produced by insertion of asilicon coated No. 4-0 nylon filament having 0.30-0.35 mm in diameterand about 17 mm in length into the ICA. The right ICA was ligatedtogether with the filament, the skin was temporarily sutured, and therats were returned to their cages. After 1.5 hours of occlusion, thecervical wound was reopened under isoflurane anesthesia, and thefilament was slightly withdrawn to allow reperfusion. The cervical woundwas closed, and the rats were returned to their cages. The experimentalcompounds were dissolved in a Tris buffer solution or a physiologicalsaline solution to produce a concentration of 1.5 to 15 mg/ml, and theprepared solutions or vehicle were intravenously administered in thequantity of 2 ml/kg immediately after the vascular occlusion andreperfusion.

Twenty-four hours after reperfusion, the rat whole brains were removedand the forebrain coronal sections were prepared in 2-mm thick from theboundary of the cerebrum and cerebellum. The slices were incubated in a1% 2,3,5-triphenyltetrazolium chloride (TTC) solution at 37° C. for 30minutes and fixed by immersion in 10% neutralized formalin. The imagesof the slices were scanned, and the area of the TTC achromatic region onthe surface was measured using image-analysis software (Win ROOF Ver.5.6, Mitani Corporation). The measured area value was multiplied by thethickness of 2 mm to determine the volume of each slice, and the sum ofthe thus-obtained volumes was defined as the total cerebral infarctvolume.

The statistical difference in cerebral infarct volume between thevehicle administered group (control group) and the compound administeredgroup was analyzed by a t-test (two-tailed) using a non-clinicalstatistical analysis system. A probability less than 0.05 was defined asa statistically significant difference. When a statistically significantdecrease in the cerebral infarct volume was observed in the compoundadministered group compared to the control group, it was determined thatthe experimental compound had a neuroprotective effect.

1. A quinolone compound represented by Formula (1):

or a salt thereof, wherein R₁ represents: (1) hydrogen, (2) C₁-C₆ alkyl,(3) halogen-substituted C₁-C₆ alkyl, (4) C₂-C₆ alkenyl, (5) C₁-C₆alkanoyl, (6) halogen-substituted C₁-C₆ alkanoyl, (7) hydroxy C₁-C₆alkyl, (8) protected hydroxy C₁-C₆ alkyl, (9) hydroxy C₁-C₆ alkanoyl,(10) protected hydroxy C₁-C₆ alkanoyl, (11) C₁-C₆ alkylthio C₁-C₆ alkyl,(12) amino C₁-C₆ alkylthio C₁-C₆ alkyl optionally having one or moreC₁-C₆ alkyl groups, (13) hydroxy C₁-C₆ alkylthio C₁-C₆ alkyl, (14)carboxy C₁-C₆ alkylthio C₁-C₆ alkyl, (15) C₁-C₆ alkoxycarbonyl C₁-C₆alkylthio C₁-C₆ alkyl, (16) amino C₁-C₆ alkylthiocarbonyl C₁-C₆ alkyloptionally having one or more C₁-C₆ alkyl groups, (17) hydroxy C₁-C₆alkylsulfonyl C₁-C₆ alkyl, (18) carboxy C₁-C₆ alkylsulfonyl C₁-C₆ alkyl,(19) C₁-C₆ alkoxycarbonyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (20) C₁-C₆alkanoyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (21) piperazinyl C₁-C₆alkylsulfonyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkylgroups on the piperazine ring, (22) piperazinylcarbonyl C₁-C₆alkylsulfonyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkylgroups on the piperazine ring, (23) C₁-C₆ alkanoyl C₁-C₆ alkyl, (24)carboxy C₁-C₆ alkyl, (25) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl, (26)piperazinyl C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl optionally having one ormore C₁-C₆ alkyl groups on the piperazine ring, (27) morpholinyl C₁-C₆alkyl, (28) oxazepanyl C₁-C₆ alkyl, (29) amino C₁-C₆ alkyl optionallyhaving one or more C₁-C₆ alkyl groups, (30) piperazyl C₁-C₆ alkyloptionally having, on the piperazine ring, one or more substituentsselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆alkyl, and pyridyl, (31) piperidyl C₁-C₆ alkyl optionally having one ormore morpholinyl groups, (32) azetidyl C₁-C₆ alkyl optionally having oneor more hydroxy groups on the azetidine ring, (33) isoindolinyl C₁-C₆alkyl optionally having one or more oxo groups, (34) amino C₁-C₆alkanoyloxy C₁-C₆ alkyl optionally having one or more substituentsselected from the group consisting of C₁-C₆ alkyl and C₁-C₆alkoxycarbonyl, (35) carbamoyl C₁-C₆ alkyl optionally having one or moresubstituents selected from C₁-C₆ alkyl; morpholinyl C₁-C₆ alkyl;piperidyl optionally having one or more substituents selected from thegroup consisting of C₁-C₆ alkyl and C₁-C₆ alkoxycarbonyl; andpiperazinyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkylgroups, (36) phosphonooxy C₁-C₆ alkyl optionally having one or morehydroxy-protecting groups, (37) phosphonooxy C₁-C₆ alkanoyloxy C₁-C₆alkyl optionally having one or more hydroxy-protecting groups, (38)benzoyloxy C₁-C₆ alkyl optionally having, on the benzene ring, one ormore substituents selected from the group consisting of hydroxy,protected hydroxy, and phosphonooxy optionally having one or morehydroxyl-protecting groups, (39) tetrahydropyranyl optionally having oneor more substituents selected from the group consisting of hydroxy,hydroxy C₁-C₆ alkyl and carboxyl, or (40) C₁-C₆ alkanoylamino C₁-C₆alkyl optionally having, on the C₁-C₆ alkanoyl group, one or moresubstituents selected from the group consisting of halogen; hydroxy;amino; C₁-C₆ alkoxycarbonylamino; piperazinyl optionally having one ormore C₁-C₆ alkoxy C₁-C₆ alkyl groups; imidazolyl; andmorpholinylpiperidyl; R₂ represents: (1) hydrogen, (2) C₁-C₆ alkyl, (3)C₁-C₆ alkanoyl, (4) hydroxy C₁-C₆ alkyl, (5) carboxy, (6) C₁-C₆alkoxycarbonyl, (7) carbamoyl optionally having one or more substituentsselected from the group consisting of C₁-C₆ alkyl; halogen-substitutedC₁-C₆ alkyl; hydroxy C₁-C₆ alkyl; piperazinyl C₁-C₆ alkyl optionallyhaving one or more C₁-C₆ alkyl groups; and morpholinyl C₁-C₆ alkyl, (8)carbamoyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkyl groups,(9) morpholinyl C₁-C₆ alkyl, (10) piperazinyl C₁-C₆ alkyl optionallyhaving one or more substituents selected from the group consisting ofC₁-C₆ alkyl and pyridyl optionally having one or more C₁-C₆ alkylgroups, (11) diazepanyl C₁-C₆ alkyl, (12) amino C₁-C₆ alkyl optionallyhaving one or more substituents selected from the group consisting ofC₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, andmorpholinyl C₁-C₆ alkyl, (13) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl, or (14)carboxy C₁-C₆ alkyl; R₃ represents phenyl, thienyl, furyl, pyrazolyl, orpyrimidinyl, wherein: the aromatic or heterocyclic ring represented byR₃ may be substituted with one or more substituents selected from thegroup consisting of the following substituents (1) to (14): (1) C₁-C₆alkyl, (2) C₁-C₆ alkoxy, (3) C₁-C₆ alkanoyl, (4) halogen, (5) hydroxy,(6) hydroxy C₁-C₆ alkyl, (7) hydroxy C₁-C₆ alkoxy, (8) protected hydroxyC₁-C₆ alkoxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆alkoxy, (11) pyrrolidinylcarbonyl, (12) carbamoyl C₁-C₆ alkoxyoptionally having one or more C₁-C₆ alkyl groups, (13) carbamoyloptionally having one or more morpholinyl C₁-C₆ alkyl groups, and (14)morpholinylpiperidylcarbonyl; R₄ and R₅ are linked to form a grouprepresented by any of the following formulae:

or a group represented by the following formula:

the group optionally having one or more substituents selected from thegroup consisting of C₁-C₆ alkyl and oxo groups; R₆ represents hydrogenor C₁-C₆ alkoxy; R₇ represents any of the following groups (1) to (11):(1) hydrogen, (2) C₁-C₆ alkoxy, (3) hydroxy C₁-C₆ alkoxy, (4) protectedhydroxy C₁-C₆ alkoxy, (5) C₁-C₆ alkoxy C₁-C₆ alkoxy, (6) carbamoyl C₁-C₆alkoxy optionally having one or more substituents selected from thegroup consisting of C₁-C₆ alkyl and morpholinyl C₁-C₆ alkyl, (7) aminooptionally having one or two substituents selected from the groupconsisting of C₁-C₆ alkyl and cyclo C₃-C₈ alkyl, (8) cyclo C₃-C₈alkyloxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆alkoxy, and (11) pyrrolidinyl; and R₆ and R₇ may be linked to form agroup represented by any of the following formulae:


2. A quinolone compound of General Formula (1) or a salt thereofaccording to claim 1, wherein: R₁ represents: (1) hydrogen, (2) C₁-C₆alkyl, (3) halogen-substituted C₁-C₆ alkyl, (4) C₂-C₆ alkenyl, (5) C₁-C₆alkanoyl, (6) halogen-substituted C₁-C₆ alkanoyl, (7) hydroxy C₁-C₆alkyl, (8) phenyl C₁-C₆ alkoxy C₁-C₆ alkyl, (9) hydroxy C₁-C₆ alkanoyl,(10) phenyl C₁-C₆ alkoxy C₁-C₆ alkanoyl, (11) C₁-C₆ alkylthio C₁-C₆alkyl, (12) amino C₁-C₆ alkylthio C₁-C₆ alkyl optionally having, on theamino group, two C₁-C₆ alkyl groups, (13) hydroxy C₁-C₆ alkylthio C₁-C₆alkyl, (14) carboxy C₁-C₆ alkylthio C₁-C₆ alkyl, (15) C₁-C₆alkoxycarbonyl C₁-C₆ alkylthio C₁-C₆ alkyl, (16) amino C₁-C₆alkylthiocarbonyl C₁-C₆ alkyl optionally having, on the amino group, twoC₁-C₆ alkyl groups, (17) hydroxy C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (18)carboxy C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (19) C₁-C₆ alkoxycarbonyl C₁-C₆alkylsulfonyl C₁-C₆ alkyl, (20) C₁-C₆ alkanoyl C₁-C₆ alkylsulfonyl C₁-C₆alkyl, (21) piperazinyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl optionallyhaving one C₁-C₆ alkyl group on the piperazine ring, (22)piperazinylcarbonyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl optionally havingone C₁-C₆ alkyl group on the piperazine ring, (23) C₁-C₆ alkanoyl C₁-C₆alkyl, (24) carboxy C₁-C₆ alkyl, (25) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl,(26) piperazinyl C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl optionally having oneC₁-C₆ alkyl group on the piperazine ring, (27) morpholinyl C₁-C₆ alkyl,(28) oxazepanyl C₁-C₆ alkyl, (29) amino C₁-C₆ alkyl optionally havingone C₁-C₆ alkyl group on the amino group, (30) piperazyl C₁-C₆ alkyloptionally having, on the piperazine ring, one substituent selected fromthe group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, andpyridyl, (31) piperidyl C₁-C₆ alkyl optionally having one morpholinylgroup on the piperidine ring, (32) azetidyl C₁-C₆ alkyl optionallyhaving one hydroxy group on the azetidine ring, (33) isoindolinyl C₁-C₆alkyl optionally having two oxo groups on the isoindoline ring, (34)amino C₁-C₆ alkanoyloxy C₁-C₆ alkyl optionally having, on the aminogroup, one or two substituents selected from the group consisting ofC₁-C₆ alkyl and C₁-C₆ alkoxycarbonyl, (35) carbamoyl C₁-C₆ alkyloptionally having, on the carbamoyl group, one substituent selected fromC₁-C₆ alkyl; morpholinyl C₁-C₆ alkyl; piperidyl optionally having onesubstituent selected from the group consisting of C₁-C₆ alkyl and C₁-C₆alkoxycarbonyl; and piperazinyl C₁-C₆ alkyl optionally having one C₁-C₆alkyl group, (36) phosphonooxy C₁-C₆ alkyl optionally having one or twoC₁-C₆ alkyl groups on the phosphonooxy group, (37) phosphonooxy C₁-C₆alkanoyloxy C₁-C₆ alkyl optionally having one or two C₁-C₆ alkyl groupson the phosphonooxy group, (38) benzoyloxy C₁-C₆ alkyl optionallyhaving, on the benzene ring, one substituent selected from the groupconsisting of hydroxy, benzyloxy, and phosphonooxy optionally having oneor two C₁-C₆ alkyl groups, (39) tetrahydropyranyl optionally havingthree hydroxy groups and one hydroxy C₁-C₆ alkyl group, or (40) C₁-C₆alkanoylamino C₁-C₆ alkyl optionally having, on the C₁-C₆ alkanoylgroup, one or two substituents selected from the group consisting ofhalogen; hydroxy; amino; C₁-C₆ alkoxycarbonylamino; piperazinyloptionally having one C₁-C₆ alkoxy C₁-C₆ alkyl group; imidazolyl; andmorpholinylpiperidyl; R₂ represents: (1) hydrogen, (2) C₁-C₆ alkyl, (3)C₁-C₆ alkanoyl, (4) hydroxy C₁-C₆ alkyl, (5) carboxy, (6) C₁-C₆alkoxycarbonyl, (7) carbamoyl optionally having one or two substituentsselected from the group consisting of C₁-C₆ alkyl; halogen-substitutedC₁-C₆ alkyl; hydroxy C₁-C₆ alkyl; piperazinyl C₁-C₆ alkyl optionallyhaving one C₁-C₆ alkyl group on the piperazine ring; and morpholinylC₁-C₆ alkyl, (8) carbamoyl C₁-C₆ alkyl optionally having one C₁-C₆ alkylgroup on the carbamoyl group, (9) morpholinyl C₁-C₆ alkyl, (10)piperazinyl C₁-C₆ alkyl optionally having, on the piperazine ring, onesubstituent selected from the group consisting of C₁-C₆ alkyl andpyridyl optionally having one C₁-C₆ alkyl group, (11) diazepanyl C₁-C₆alkyl, or (12) amino C₁-C₆ alkyl optionally having, on the amino group,one or two substituents selected from the group consisting of C₁-C₆alkyl, halogen-substituted C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, andmorpholinyl C₁-C₆ alkyl; R₃ represents phenyl, thienyl, furyl,pyrazolyl, or pyrimidinyl, wherein: the aromatic or heterocyclic ringrepresented by R₃ may be substituted with one or two substituentsselected from the group consisting of the following substituents (1) to(14): (1) C₁-C₆ alkyl, (2) C₁-C₆ alkoxy, (3) C₁-C₆ alkanoyl, (4)halogen, (5) hydroxy, (6) hydroxy C₁-C₆ alkyl, (7) hydroxy C₁-C₆ alkoxy,(8) tetrahydropyranyloxy C₁-C₆ alkoxy, (9) carboxy C₁-C₆ alkoxy, (10)C₁-C₆ alkoxycarbonyl C₁-C₆ alkoxy, (11) pyrrolidinylcarbonyl, (12)carbamoyl C₁-C₆ alkoxy optionally having one C₁-C₆ alkyl group on thecarbamoyl group, (13) carbamoyl optionally having one morpholinyl C₁-C₆alkyl group, and (14) morpholinylpiperidylcarbonyl; R₆ representshydrogen or C₁-C₆ alkoxy; and R₇ represents any of the following groups(1) to (11): (1) hydrogen, (2) C₁-C₆ alkoxy, (3) hydroxy C₁-C₆ alkoxy,(4) benzyloxy C₁-C₆ alkoxy, (5) C₁-C₆ alkoxy C₁-C₆ alkoxy, (6) carbamoylC₁-C₆ alkoxy optionally having, on the carbamoyl group, one substituentselected from the group consisting of C₁-C₆ alkyl and morpholinyl C₁-C₆alkyl, (7) amino optionally having two substituents selected from thegroup consisting of C₁-C₆ alkyl and cyclo C₃-C₈ alkyl, (8) cyclo C₃-C₈alkyloxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆alkoxy, and (11) pyrrolidinyl.
 3. A quinolone compound of GeneralFormula (1) or a salt thereof according to claim 2, wherein R₁represents: (1) hydrogen, (2) C₁-C₆ alkyl, (3) halogen-substituted C₁-C₆alkyl, (24) carboxy C₁-C₆ alkyl, (25) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl,(27) morpholinyl C₁-C₆ alkyl, (28) oxazepanyl C₁-C₆ alkyl, (30)piperazyl C₁-C₆ alkyl optionally having, on the piperazine ring, oneC₁-C₆ alkoxy C₁-C₆ alkyl, (31) piperidyl C₁-C₆ alkyl, (35) carbamoylC₁-C₆ alkyl optionally having one morpholinyl C₁-C₆ alkyl, or (36)phosphonooxy C₁-C₆ alkyl optionally having one or two C₁-C₆ alkylgroups; R₂ represents: (1) hydrogen, or (2) C₁-C₆ alkyl, R₃ representsphenyl, thienyl, or furyl, wherein: the aromatic or heterocyclic ringrepresented by R₃ may be substituted with one C₁-C₆ alkoxy group, R₆represents hydrogen; and R₇ represents C₁-C₆ alkoxy.
 4. A quinolonecompound represented by General Formula (1):

or a salt thereof, wherein R₁ represents: (1) hydrogen, (2) C₁-C₆ alkyl,(3) halogen-substituted C₁-C₆ alkyl, (4) C₂-C₆ alkenyl, (5) C₁-C₆alkanoyl, (6) halogen-substituted C₁-C₆ alkanoyl, (7) hydroxy C₁-C₆alkyl, (8) protected hydroxy C₁-C₆ alkyl, (9) hydroxy C₁-C₆ alkanoyl,(10) protected hydroxy C₁-C₆ alkanoyl, (11) lower alkylthio C₁-C₆ alkyl,(12) amino C₁-C₆ alkylthio C₁-C₆ alkyl optionally having one or moreC₁-C₆ alkyl groups, (13) hydroxy C₁-C₆ alkylthio C₁-C₆ alkyl, (14)carboxy C₁-C₆ alkylthio C₁-C₆ alkyl, (15) C₁-C₆ alkoxycarbonyl C₁-C₆alkylthio C₁-C₆ alkyl, (16) amino C₁-C₆ alkylthiocarbonyl C₁-C₆ alkyloptionally having one or more C₁-C₆ alkyl groups, (17) hydroxy C₁-C₆alkylsulfonyl C₁-C₆ alkyl, (18) carboxy C₁-C₆ alkylsulfonyl C₁-C₆ alkyl,(19) C₁-C₆ alkoxycarbonyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (20) C₁-C₆alkanoyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (21) piperazinyl C₁-C₆alkylsulfonyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkylgroups on the piperazine ring, (22) piperazinylcarbonyl C₁-C₆alkylsulfonyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkylgroups on the piperazine ring, (23) C₁-C₆ alkanoyl C₁-C₆ alkyl, (24)carboxy C₁-C₆ alkyl, (25) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl, (26)piperazinyl C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl optionally having one ormore C₁-C₆ alkyl groups on the piperazine ring, (27) morpholinyl C₁-C₆alkyl, (28) oxazepanyl C₁-C₆ alkyl, (29) amino C₁-C₆ alkyl optionallyhaving one or more C₁-C₆ alkyl groups, (30) piperazyl C₁-C₆ alkyloptionally having, on the piperazine ring, one or more substituentsselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆alkyl, and pyridyl, (31) piperidyl C₁-C₆ alkyl optionally having one ormore morpholinyl groups, (32) azetidyl C₁-C₆ alkyl optionally having oneor more hydroxy groups on the azetidine ring, (33) isoindolinyl C₁-C₆alkyl optionally having one or more oxo groups, (34) amino C₁-C₆alkanoyloxy C₁-C₆ alkyl optionally having one or more substituentsselected from the group consisting of C₁-C₆ alkyl and C₁-C₆alkoxycarbonyl, (35) carbamoyl C₁-C₆ alkyl optionally having one or moresubstituents selected from C₁-C₆ alkyl; morpholinyl C₁-C₆ alkyl;piperidyl optionally having one or more substituents selected from thegroup consisting of C₁-C₆ alkyl and C₁-C₆ alkoxycarbonyl; andpiperazinyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkylgroups, (36) phosphonooxy C₁-C₆ alkyl optionally having one or morehydroxy-protecting groups, (37) phosphonooxy C₁-C₆ alkanoyloxy C₁-C₆alkyl optionally having one or more hydroxy-protecting groups, (38)benzoyloxy C₁-C₆ alkyl optionally having, on the benzene ring, one ormore substituents selected from the group consisting of hydroxy,protected hydroxy, and phosphonooxy optionally having one or morehydroxyl-protecting groups, (39) tetrahydropyranyl optionally having oneor more substituents selected from the group consisting of hydroxy,hydroxy C₁-C₆ alkyl and carboxyl, or (40) C₁-C₆ alkanoylamino C₁-C₆alkyl optionally having, on the C₁-C₆ alkanoyl group, one or moresubstituents selected from the group consisting of halogen; hydroxy;amino; C₁-C₆ alkoxycarbonylamino; piperazinyl optionally having one ormore C₁-C₆ alkoxy C₁-C₆ alkyl groups; imidazolyl; andmorpholinylpiperidyl; R₂ represents: (1) hydrogen, (2) C₁-C₆ alkyl, (3)C₁-C₆ alkanoyl, (4) hydroxy C₁-C₆ alkyl, (5) carboxy, (6) C₁-C₆alkoxycarbonyl, (7) carbamoyl optionally having one or more substituentsselected from the group consisting of C₁-C₆ alkyl; halogen-substitutedC₁-C₆ alkyl; hydroxy C₁-C₆ alkyl; piperazinyl C₁-C₆ alkyl optionallyhaving one or more C₁-C₆ alkyl groups; and morpholinyl C₁-C₆ alkyl, (8)carbamoyl C₁-C₆ alkyl optionally having one or more C₁-C₆ alkyl groups,(9) morpholinyl C₁-C₆ alkyl, (10) piperazinyl C₁-C₆ alkyl optionallyhaving one or more substituents selected from the group consisting ofC₁-C₆ alkyl and pyridyl optionally having one or more C₁-C₆ alkylgroups, (11) diazepanyl C₁-C₆ alkyl, (12) amino C₁-C₆ alkyl optionallyhaving one or more substituents selected from the group consisting ofC₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, andmorpholinyl C₁-C₆ alkyl, (13) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl, or (14)carboxy C₁-C₆ alkyl; R₃ represents phenyl, thienyl, furyl, pyrazolyl, orpyrimidinyl, wherein: the aromatic or heterocyclic ring represented byR₃ may be substituted with one or more substituents selected from thegroup consisting of the following substituents (1) to (14): (1) C₁-C₆alkyl, (2) C₁-C₆ alkoxy, (3) C₁-C₆ alkanoyl, (4) halogen, (5) hydroxy,(6) hydroxy C₁-C₆ alkyl, (7) hydroxy C₁-C₆ alkoxy, (8) protected hydroxyC₁-C₆ alkoxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆alkoxy, (11) pyrrolidinylcarbonyl, (12) carbamoyl C₁-C₆ alkoxyoptionally having one or more C₁-C₆ alkyl groups, (13) carbamoyloptionally having one or more morpholinyl C₁-C₆ alkyl groups, and (14)morpholinylpiperidylcarbonyl; R₄ represents halogen, C₁-C₆ alkyl, orC₁-C₆ alkoxy; R₅ represents hydrogen or halogen; or R₄ and R₅ are linkedto form a group represented by any of the following formulae:

or a group represented by the following formula:

the group optionally having one or more substituents selected from thegroup consisting of C₁-C₆ alkyl and oxo groups; and R₆ and R₇ are linkedto form a group represented by any of the following formulae:


5. A quinolone compound of General Formula (1) or a salt thereofaccording to claim 4, wherein R₁ represents: (1) hydrogen, (2) C₁-C₆alkyl, or (36) phosphonooxy C₁-C₆ alkyl optionally having one or twoC₁-C₆ alkyl groups; R₂ represents hydrogen, R₃ represents phenyl whereinthe aromatic or heterocyclic ring represented by R₃ may be substitutedwith one C₁-C₆ alkoxy group; R₄ represents C₁-C₆ alkyl, or C₁-C₆ alkoxy;and R₅ represents hydrogen.
 6. A quinolone compound represented byGeneral Formula (1):

or a salt thereof, wherein R₁ represents: (3) halogen-substituted C₁-C₆alkyl, (4) C₂-C₆ alkenyl, (5) C₁-C₆ alkanoyl, (6) halogen-substitutedC₁-C₆ alkanoyl, (7) hydroxy C₁-C₆ alkyl, (8) phenyl C₁-C₆ alkoxy C₁-C₆alkyl, (9) hydroxy C₁-C₆ alkanoyl, (10) phenyl C₁-C₆ alkoxy C₁-C₆alkanoyl, (11) C₁-C₆ alkylthio C₁-C₆ alkyl, (12) amino C₁-C₆ alkylthioC₁-C₆ alkyl optionally having one or two C₁-C₆ alkyl groups, (13)hydroxy C₁-C₆ alkylthio C₁-C₆ alkyl, (14) carboxy C₁-C₆ alkylthio C₁-C₆alkyl, (15) C₁-C₆ alkoxycarbonyl C₁-C₆ alkylthio C₁-C₆ alkyl, (16) aminoC₁-C₆ alkylthiocarbonyl C₁-C₆ alkyl optionally having one or two C₁-C₆alkyl groups, (17) hydroxy C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (18) carboxyC₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (19) C₁-C₆ alkoxycarbonyl C₁-C₆alkylsulfonyl C₁-C₆ alkyl, (20) C₁-C₆ alkanoyl C₁-C₆ alkylsulfonyl C₁-C₆alkyl, (21) piperazinyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl optionallyhaving one C₁-C₆ alkyl group on the piperazine ring, (22)piperazinylcarbonyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl optionally havingone C₁-C₆ alkyl group on the piperazine ring, (23) C₁-C₆ alkanoyl C₁-C₆alkyl, (24) carboxy C₁-C₆ alkyl, (25) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl,(26) piperazinyl C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl optionally having oneC₁-C₆ alkyl group on the piperazine ring, (27) morpholinyl C₁-C₆ alkyl,(28) oxazepanyl C₁-C₆ alkyl, (29) amino C₁-C₆ alkyl optionally havingone or two C₁-C₆ alkyl groups, (30) piperazyl C₁-C₆ alkyl optionallyhaving, on the piperazine ring, one substituent selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, and pyridyl, (31)piperidyl C₁-C₆ alkyl optionally having one morpholinyl group, (32)azetidyl C₁-C₆ alkyl optionally having one hydroxy group on theazetidine ring, (33) isoindolinyl C₁-C₆ alkyl optionally having one ortwo oxo groups, (34) amino C₁-C₆ alkanoyloxy C₁-C₆ alkyl optionallyhaving one or two substituents selected from the group consisting ofC₁-C₆ alkyl and C₁-C₆ alkoxycarbonyl, (35) carbamoyl C₁-C₆ alkyloptionally having one or two substituents selected from C₁-C₆ alkyl;morpholinyl C₁-C₆ alkyl; piperidyl optionally having one substituentselected from the group consisting of C₁-C₆ alkyl and C₁-C₆alkoxycarbonyl; and piperazinyl C₁-C₆ alkyl optionally having one C₁-C₆alkyl group, (36) phosphonooxy C₁-C₆ alkyl optionally having one or twoC₁-C₆ alkyl groups on the phosphonooxy group, (37) phosphonooxy C₁-C₆alkanoyloxy C₁-C₆ alkyl optionally having one or two C₁-C₆ alkyl groupson the phosphonooxy group, (38) benzoyloxy C₁-C₆ alkyl optionallyhaving, on the benzene ring, one substituent selected from the groupconsisting of hydroxy, benzyloxy, and phosphonooxy optionally having oneor two C₁-C₆ alkyl groups, (39) tetrahydropyranyl optionally having oneto four substituents selected from the group consisting of hydroxy,hydroxy C₁-C₆ alkyl and carboxyl, or (40) C₁-C₆ alkanoylamino C₁-C₆alkyl optionally having, on the C₁-C₆ alkanoyl group, one or twosubstituents selected from the group consisting of halogen; hydroxy;amino; C₁-C₆ alkoxycarbonylamino; piperazinyl optionally having oneC₁-C₆ alkoxy C₁-C₆ alkyl group; imidazolyl; and morpholinylpiperidyl; R₂represents: (1) hydrogen, (2) C₁-C₆ alkyl, (3) C₁-C₆ alkanoyl, (4)hydroxy C₁-C₆ alkyl, (5) carboxy, (6) C₁-C₆ alkoxycarbonyl, (7)carbamoyl optionally having one or two substituents selected from thegroup consisting of C₁-C₆ alkyl; halogen-substituted C₁-C₆ alkyl;hydroxy C₁-C₆ alkyl; piperazinyl C₁-C₆ alkyl optionally having one C₁-C₆alkyl group on the piperazine ring; and morpholinyl C₁-C₆ alkyl, (8)carbamoyl C₁-C₆ alkyl optionally having one C₁-C₆ alkyl group on thecarbamoyl group, (9) morpholinyl C₁-C₆ alkyl, (10) piperazinyl C₁-C₆alkyl optionally having, on the piperazine ring, one substituentselected from the group consisting of C₁-C₆ alkyl and pyridyl optionallyhaving one C₁-C₆ alkyl group, (11) diazepanyl C₁-C₆ alkyl, or (12) aminoC₁-C₆ alkyl optionally having, on the amino group, one or twosubstituents selected from the group consisting of C₁-C₆ alkyl,halogen-substituted C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, and morpholinylC₁-C₆ alkyl; R₃ represents phenyl, thienyl, furyl, pyrazolyl, orpyrimidinyl, wherein: the aromatic or heterocyclic ring represented byR₃ may be substituted with one or two substituents selected from thegroup consisting of the following substituents (1) to (14): (1) C₁-C₆alkyl, (2) C₁-C₆ alkoxy, (3) C₁-C₆ alkanoyl, (4) halogen, (5) hydroxy,(6) hydroxy C₁-C₆ alkyl, (7) hydroxy C₁-C₆ alkoxy, (8)tetrahydropyranyloxy C₁-C₆ alkoxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆alkoxycarbonyl C₁-C₆ alkoxy, (11) pyrrolidinylcarbonyl, (12) carbamoylC₁-C₆ alkoxy optionally having one or two C₁-C₆ alkyl groups, (13)carbamoyl optionally having one morpholinyl C₁-C₆ alkyl group, and (14)morpholinylpiperidylcarbonyl; R₄ represents halogen; R₅ representshydrogen or halogen; R₆ represents hydrogen or C₁-C₆ alkoxy; and R₇represents any of the following groups (2) to (11): (2) C₁-C₆ alkoxy,(3) hydroxy C₁-C₆ alkoxy, (4) benzyloxy C₁-C₆ alkoxy, (5) C₁-C₆ alkoxyC₁-C₆ alkoxy, (6) carbamoyl C₁-C₆ alkoxy optionally having onesubstituent selected from the group consisting of C₁-C₆ alkyl andmorpholinyl C₁-C₆ alkyl, (7) amino optionally having one or twosubstituents selected from the group consisting of C₁-C₆ alkyl and cycloC₃-C₈ alkyl, (8) cyclo C₃-C₈ alkyloxy, (9) carboxy C₁-C₆ alkoxy, (10)C₁-C₆ alkoxycarbonyl C₁-C₆ alkoxy, and (11) pyrrolidinyl.
 7. A quinolonecompound of General Formula (1) or a salt thereof according to claim 6,wherein R₁ represents: (3) halogen-substituted C₁-C₆ alkyl, (4) C₂-C₆alkenyl, (5) C₁-C₆ alkanoyl, (6) halogen-substituted C₁-C₆ alkanoyl, (8)benzyloxy C₁-C₆ alkyl, (10) benzyloxy C₁-C₆ alkanoyl, (11) C₁-C₆alkylthio C₁-C₆ alkyl, (12) amino C₁-C₆ alkylthio C₁-C₆ alkyl optionallyhaving one or two C₁-C₆ alkyl groups, (13) hydroxy C₁-C₆ alkylthio C₁-C₆alkyl, (14) carboxy C₁-C₆ alkylthio C₁-C₆ alkyl, (15) C₁-C₆alkoxycarbonyl C₁-C₆ alkylthio C₁-C₆ alkyl, (16) amino C₁-C₆alkylthiocarbonyl C₁-C₆ alkyl optionally having one or two C₁-C₆ alkylgroups, (17) hydroxy C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (18) carboxy C₁-C₆alkylsulfonyl C₁-C₆ alkyl, (19) C₁-C₆ alkoxycarbonyl C₁-C₆ alkylsulfonylC₁-C₆ alkyl, (20) C₁-C₆ alkanoyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, (21)piperazinyl C₁-C₆ alkylsulfonyl C₁-C₆ alkyl optionally having one C₁-C₆alkyl group on the piperazine ring, (22) piperazinylcarbonyl C₁-C₆alkylsulfonyl C₁-C₆ alkyl optionally having one C₁-C₆ alkyl group on thepiperazine ring, (24) carboxy C₁-C₆ alkyl, (25) C₁-C₆ alkoxycarbonylC₁-C₆ alkyl, (26) piperazinyl C₁-C₆ alkoxycarbonyl C₁-C₆ alkyloptionally having one C₁-C₆ alkyl group on the piperazine ring, (27)morpholinyl C₁-C₆ alkyl, (29) amino C₁-C₆ alkyl optionally having one ortwo C₁-C₆ alkyl groups, (30) piperazyl C₁-C₆ alkyl optionally having, onthe piperazine ring, one substituent selected from the group consistingof C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, and pyridyl, (31) piperidylC₁-C₆ alkyl optionally having one morpholinyl group, (32) azetidyl C₁-C₆alkyl optionally having one hydroxy group on the azetidine ring, (33)isoindolinyl C₁-C₆ alkyl optionally having one or two oxo groups, (34)amino C₁-C₆ alkanoyloxy C₁-C₆ alkyl optionally having one or twosubstituents selected from the group consisting of C₁-C₆ alkyl and C₁-C₆alkoxycarbonyl, (35) carbamoyl C₁-C₆ alkyl optionally having one or twosubstituents selected from C₁-C₆ alkyl; morpholinyl C₁-C₆ alkyl;piperidyl optionally having one substituent selected from the groupconsisting of C₁-C₆ alkyl and C₁-C₆ alkoxycarbonyl; and piperazinylC₁-C₆ alkyl optionally having one C₁-C₆ alkyl group, (36) phosphonooxyC₁-C₆ alkyl optionally having one or two C₁-C₆ alkyl groups on thephosphonooxy group, (37) phosphonooxy C₁-C₆ alkanoyloxy C₁-C₆ alkyloptionally having one or two C₁-C₆ alkyl groups on the phosphonooxygroup, (38) benzoyloxy C₁-C₆ alkyl optionally having, on the benzenering, one substituent selected from the group consisting of hydroxy,benzyloxy, and phosphonooxy optionally having one or two C₁-C₆ alkylgroups, (39) tetrahydropyranyl optionally having one or foursubstituents selected from the group consisting of hydroxy, hydroxyC₁-C₆ alkyl and carboxyl, or (40) C₁-C₆ alkanoylamino C₁-C₆ alkyloptionally having, on the C₁-C₆ alkanoyl group, one or two substituentsselected from the group consisting of halogen; hydroxy; amino; C₁-C₆alkoxycarbonylamino; piperazinyl optionally having one C₁-C₆ alkoxyC₁-C₆ alkyl group; imidazolyl; and morpholinylpiperidyl; R₂ representshydrogen; R₃ represents phenyl, pyrazolyl, or pyrimidinyl, wherein: thearomatic or heterocyclic ring represented by R₃ may be substituted withone or two substituents selected from the group consisting of thefollowing substituents (1), (2), (4), (5), (7), (8), (10), (11), and(12): (1) C₁-C₆ alkyl, (2) C₁-C₆ alkoxy, (4) halogen, (5) hydroxy, (7)hydroxy C₁-C₆ alkoxy, (8) tetrahydropyranyloxy C₁-C₆ alkoxy, (10) C₁-C₆alkoxycarbonyl C₁-C₆ alkoxy, (11) pyrrolidinylcarbonyl, and (12)carbamoyl C₁-C₆ alkoxy; R₄ represents halogen; R₅ represents hydrogen orhalogen; R₆ represents hydrogen; and R₇ represents any of the followinggroups (2), (7), (8) and (11): (2) C₁-C₆ alkoxy, (7) amino optionallyhaving one or two substituents selected from the group consisting ofC₁-C₆ alkyl and cyclo C₃-C₈ alkyl, (8) cyclo C₃-C₈ alkyloxy, and (11)pyrrolidinyl.
 8. A quinolone compound represented by General Formula(1):

or a salt thereof, wherein R₁ represents: (1) hydrogen, or (2) C₁-C₆alkyl; R₂ represents: (3) C₁-C₆ alkanoyl, (4) hydroxy C₁-C₆ alkyl, (5)carboxy, (6) C₁-C₆ alkoxycarbonyl, (7) carbamoyl optionally having oneor two substituents selected from the group consisting of C₁-C₆ alkyl;halogen-substituted C₁-C₆ alkyl; hydroxy C₁-C₆ alkyl; piperazinyl C₁-C₆alkyl optionally having one C₁-C₆ alkyl group; and morpholinyl C₁-C₆alkyl, (8) carbamoyl C₁-C₆ alkyl optionally having one C₁-C₆ alkylgroup, (9) morpholinyl C₁-C₆ alkyl, (10) piperazinyl C₁-C₆ alkyloptionally having one substituent selected from the group consisting ofC₁-C₆ alkyl and pyridyl optionally having one C₁-C₆ alkyl group, (11)diazepanyl C₁-C₆ alkyl, (12) amino C₁-C₆ alkyl optionally having one ortwo substituents selected from the group consisting of C₁-C₆ alkyl,halogen-substituted C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, and morpholinylC₁-C₆ alkyl, (13) C₁-C₆ alkoxycarbonyl C₁-C₆ alkyl, or (14) carboxyC₁-C₆ alkyl; R₃ represents phenyl, thienyl, furyl, pyrazolyl, orpyrimidinyl, wherein: the aromatic or heterocyclic ring represented byR₃ is substituted with one substituent selected from the groupconsisting of the following substituents (1) to (14): (1) C₁-C₆ alkyl,(2) C₁-C₆ alkoxy, (3) C₁-C₆ alkanoyl, (4) halogen, (5) hydroxy, (6)hydroxy C₁-C₆ alkyl, (7) hydroxy C₁-C₆ alkoxy, (8) protected hydroxyC₁-C₆ alkoxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆alkoxy, (11) pyrrolidinylcarbonyl, (12) carbamoyl C₁-C₆ alkoxyoptionally having one C₁-C₆ alkyl group, (13) carbamoyl optionallyhaving one morpholinyl C₁-C₆ alkyl group, and (14)morpholinylpiperidylcarbonyl; R₄ represents halogen, C₁-C₆ alkyl, orC₁-C₆ alkoxy; R₅ represents hydrogen or halogen; R₆ represents hydrogenor C₁-C₆ alkoxy; and R₇ represents any of the following groups (1) to(11): (1) hydrogen, (2) C₁-C₆ alkoxy, (3) hydroxy C₁-C₆ alkoxy, (4)benzyloxy C₁-C₆ alkoxy, (5) C₁-C₆ alkoxy C₁-C₆ alkoxy, (6) carbamoylC₁-C₆ alkoxy optionally having one substituent selected from the groupconsisting of C₁-C₆ alkyl and morpholinyl C₁-C₆ alkyl, (7) aminooptionally having one or two substituents selected from the groupconsisting of C₁-C₆ alkyl and cyclo C₃-C₈ alkyl, (8) cyclo C₃-C₈alkyloxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆alkoxy, and (11) pyrrolidinyl.
 9. A quinolone compound of GeneralFormula (1) or a salt thereof according to claim 8, wherein R₁represents hydrogen; R₂ represents: (3) C₁-C₆ alkanoyl, (4) hydroxyC₁-C₆ alkyl, (5) carboxy, (6) C₁-C₆ alkoxycarbonyl, (7) carbamoyloptionally having one or two substituents selected from the groupconsisting of C₁-C₆ alkyl; halogen-substituted C₁-C₆ alkyl; hydroxyC₁-C₆ alkyl; piperazinyl C₁-C₆ alkyl optionally having one C₁-C₆ alkylgroup; and morpholinyl C₁-C₆ alkyl, (8) carbamoyl C₁-C₆ alkyl optionallyhaving one C₁-C₆ alkyl group, (9) morpholinyl C₁-C₆ alkyl, (10)piperazinyl C₁-C₆ alkyl optionally having one substituent selected fromthe group consisting of C₁-C₆ alkyl and pyridyl optionally having oneC₁-C₆ alkyl group, (11) diazepanyl C₁-C₆ alkyl, (12) amino C₁-C₆ alkyloptionally having one or two substituents selected from the groupconsisting of C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl, hydroxyC₁-C₆ alkyl, and morpholinyl C₁-C₆ alkyl, or (14) carboxy C₁-C₆ alkyl;R₃ represents phenyl, wherein: the phenyl represented by R₃ issubstituted with one C₁-C₆ alkoxy group, R₄ represents halogen; R₅represents hydrogen; R₆ represents hydrogen; and R₇ represents C₁-C₆alkoxy.
 10. A quinolone compound represented by General Formula (1):

or a salt thereof, wherein R₁ represents: (1) hydrogen, or (2) C₁-C₆alkyl; R₂ represents hydrogen; R₃ represents phenyl, thienyl, furyl,pyrazolyl, or pyrimidinyl, wherein: the aromatic or heterocyclic ringrepresented by R₃ is substituted with one substituent selected from thegroup consisting of the following substituents (7), (8), (9), (10),(11), (12), (13) and (14): (7) hydroxy C₁-C₆ alkoxy, (8) benzyloxy C₁-C₆alkoxy, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆alkoxy, (11) pyrrolidinylcarbonyl, (12) carbamoyl C₁-C₆ alkoxyoptionally having one C₁-C₆ alkyl group, (13) carbamoyl optionallyhaving one morpholinyl C₁-C₆ alkyl group, and (14)morpholinylpiperidylcarbonyl; R₄ represents halogen; R₅ representshydrogen or halogen; R₆ represents hydrogen or C₁-C₆ alkoxy; and R₇represents any of the following groups (1) to (11): (1) hydrogen, (2)C₁-C₆ alkoxy, (3) hydroxy C₁-C₆ alkoxy, (4) benzyloxy C₁-C₆ alkoxy, (5)C₁-C₆ alkoxy C₁-C₆ alkoxy, (6) carbamoyl C₁-C₆ alkoxy optionally havingone substituent selected from the group consisting of C₁-C₆ alkyl andmorpholinyl C₁-C₆ alkyl, (7) amino optionally having one or twosubstituents selected from the group consisting of C₁-C₆ alkyl and cycloC₃-C₈ alkyl, (8) cyclo C₃-C₈ alkyloxy, (9) carboxy C₁-C₆ alkoxy, (10)C₁-C₆ alkoxycarbonyl C₁-C₆ alkoxy, and (11) pyrrolidinyl.
 11. Aquinolone compound of General Formula (1) or a salt thereof according toclaim 10, wherein R₁ represents hydrogen; R₃ represents phenyl, wherein:the phenyl represented by R₃ may be substituted with one substituentselected from the group consisting of the following substituents (7) to(14): (7) hydroxy C₁-C₆ alkoxy, (8) benzyloxy C₁-C₆ alkoxy, (9) carboxyC₁-C₆ alkoxy, (10) C₁-C₆ alkoxycarbonyl C₁-C₆ alkoxy, (11)pyrrolidinylcarbonyl, (12) carbamoyl C₁-C₆ alkoxy optionally having oneC₁-C₆ alkyl group, (13) carbamoyl optionally having one morpholinylC₁-C₆ alkyl group, and (14) morpholinylpiperidylcarbonyl; R₄ representshalogen; R₅ represents hydrogen; R₆ represents hydrogen; and R₇represents any of the following groups (2) and (11): (2) C₁-C₆ alkoxy;and (11) pyrrolidinyl.
 12. A quinolone compound represented by GeneralFormula (1):

or a salt thereof, wherein R₁ represents: (1) hydrogen or (2) C₁-C₆alkyl; R₂ represents hydrogen; R₃ represents phenyl, wherein: the phenylrepresented by R₃ is substituted with one C₁-C₆ alkoxy, R₄ representshalogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy; R₅ represents hydrogen orhalogen; R₆ represents hydrogen or C₁-C₆ alkoxy; and R₇ represents anyof the following groups (4), (6), (9), (10) and (11): (4) benzyloxyC₁-C₆ alkoxy, (6) carbamoyl C₁-C₆ alkoxy optionally having onesubstituent selected from the group consisting of C₁-C₆ alkyl andmorpholinyl C₁-C₆ alkyl, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆alkoxycarbonyl C₁-C₆ alkoxy, and (11) pyrrolidinyl.
 13. A quinolonecompound of General Formula (1) or a salt thereof according to claim 12,wherein R₁ represents hydrogen; R₃ represents phenyl, wherein: thephenyl represented by R₃ may be substituted with one C₁-C₆ alkoxy, R₄represents halogen; R₅ represents hydrogen; R₆ represents hydrogen; andR₇ represents any of the following groups (4), (6), (9), (10) and (11):(4) benzyloxy C₁-C₆ alkoxy, (6) carbamoyl C₁-C₆ alkoxy optionally havingone substituent selected from the group consisting of C₁-C₆ alkyl andmorpholinyl C₁-C₆ alkyl, (9) carboxy C₁-C₆ alkoxy, (10) C₁-C₆alkoxycarbonyl C₁-C₆ alkoxy, and (11) pyrrolidinyl.
 14. A process forproducing a quinolone compound represented by Formula (1b):

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined in claim 1, 5, 7, 9,11 or 13, and R₁′ is a group represented by R₁ as defined in claim 1, 5,7, 9, 11 or 13 other than hydrogen, or a salt thereof; the processcomprising reacting a compound represented by the formula:R₁′—X₂ wherein X₂ represents a group that undergoes the samesubstitution reaction as that of a halogen or a halogen atom, with acompound represented by the formula:

wherein R₂, R₃, R₄, R₅, R₆ and R₇ are as defined in claim 1, 5, 7, 9, 11or
 13. 15. A quinolone compound according to claim 1, selected from thegroup consisting of the following compounds:


16. A quinolone compound according to claim 4, selected from the groupconsisting of the following compounds:


17. A quinolone compound according to claim 6, selected from the groupconsisting of the following compounds: